Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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CYSTEINE PROTEASE INHIBITORS
BACKGROUND OF THE INVENTION
Field of Invention
The present invention is directed to compounds that are inhibitors of cysteine
proteases, in particular Cathepsins B, K, L, F, and S and are therefore useful
in treating
diseases mediated by these proteases. The present invention is directed to
pharmaceutical
compositions comprising these compounds and processes for preparing them.
State of the Art
Cysteine proteases represent a class of peptidases characterized by the
presence of a
cysteine residue in the catalytic site of the enzyme. Cysteine proteases are
associated with
the normal degradation and processing of proteins. The aberrant activity of
cysteine
, proteases, e.g., as a result of increased expression or enhanced activation,
however, may
' have pathological consequences. In this regard, certain cysteine proteases
are associated
with a number of disease states, including arthritis, muscular dystrophy,
inflammation,
tumor invasion, glomerulonephritis, malaria, periodontal disease,
metachromatic
leukodystrophy and others. For example, increased cathepsin B levels and
redistribution of
~ , the enzyme are found in tumors; thus, suggesting a role for the enzyme in
tumor invasion
and metastasis. In addition, aberrant cathepsin B activity is implicated in
such disease states
as rheumatoid arthritis, osteoarthritis, pneumocystis carinii, acute
pancreatitis, inflammatory
airway disease and bone and joint disorders.
The prominent expression of Cathepsin K in osteoclasts and osteoclast-related
. . multinucleated cells and its high collagenolytic activity suggest that the
enzyme is involved
in ososteoclast-mediated bone resorption and, hence, in bone abnormalities
such as occurs
in osteoporosis. In addition, Cathepsin K expression in the lung and its
elastinolytic activity
suggest that the enzyme plays a role in pulmonary disorders as well.
Cathepsin L is implicated in normal lysosomal proteolysis as well as several
disease
. states, including, but not limited to, metastasis of melanomas. Cathepsin S
is implicated in
Alzheimer's disease and certain autoimmune disorders, including, but not
limited to juvenile
onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease,
myasthenia gravis,
systemic lupus erythematosus, rheumatoid arthritis and Hashimoto's
thyroiditis. In addition,
Cathepsin S is implicated in allergic disorders, including, but not limited to
asthma; and
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allogeneic immune reponses, including, but not limited to, rejection of organ
transplants or
tissue grafts.
Another cysteine protease, Cathepsin F, has been found in macrophages and is
I believed to be involved in antigen processing. It is believed that Cathepsin
F is stimulated
5. in lung macrophages and possibly in other antigen presenting cells and
therefore could play
a role in airway inflammation (see G. P. Shi et al, J. Exp. Med. 191,1177,
2000)
In view of the number of diseases wherein it is recognized that an increase in
cysteine protease activity contributes to the pathology and/or symptomatology
of the
disease, molecules which inhibit the activity of this class of enzymes, in
particular
10. molecules which are inhibitors of Cathepsins B, I~, L, F, and/or S, will
therefore be useful
~s therapeutic agents.
SUMMARY OF THE INVENTION
In one aspect, this invention is directed to a compound of Formula I:
- ~ R2 R2a H R~ o R~ ~
.. . R~ H II N 13 Ra
15 ~ O R
I
wherein:
Rl is a group of formula:
(i)
Y X
\ /
Za-Zb ~_
(ii)
. . Xa
_ c_
Z
\ /
Za-Zb
. Xb
(111)
Xa
\ / \ / ~_
Xbr ;
(iv)
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X
Y
i
Y X
~~Q
- (vi)
. . Xa
Q
. Xb
(V11)
' X
- Y
(viii)
. . R5
,..
. Rs
- (ix)
R$
R
Rs ~ ~ ~_
(xi)
Y
HOZC
~a-~b ~-
. ~ X
(X11)
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(xiii)
(xiv)
X
HOZC
\ / \ / ~_
Y
Y
H02C~ Za-
\ / \ / ~_
x
COOH
HO~C~ Za-
\ / \ / ~_
s. x
(xv)
Rg
O.~ Q ~-.
(xvi)
Y X
\
, (xvii) 1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)pyrazol-3-yl;
(xviii) 1-methyl-3-trifluoro-1H-thieno-[2,3-c]-pyrazol-5-yl;
(xix) 4-(3,5-dimethyloxazol-4-yl)phenyl;
(xx) 4-(5-carboxy-2-methylthiophen-3-yl)phenyl;
. (xxi) 3-vinylphenyl;
15. (.~xii) 4-phenoxyphenyl;
(viii) 4-acetylarnino-3-methylphenyl; or
(xxiv) 4-morpholin-4-ylphenyl;
where:
Za is -CX- or N- and Zb and Z~ are independently selected from -CH- and N-
provided that if an Rl group contains Za, Zb, and Z° simultaneously
then, when Z° is N-,
.then Za is N- or -CX- and Zb is -CH-; and when Zb is N- then both Za and
Z° cannot be -
N- simultaneously;
Q is NR- where R is hydrogen or alkyl, -O-, or -S-;
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Q' is -CH- or N-;
X and Y are independently selected from hydrogen, halo, alkyl, alkoxy,
haloalkyl, or
haloalkoxy provided that both X and Y are not simultaneously hydrogen;
Xa and Xb are independently selected from alkyl, halo, alkoxy, haloalkyl, or
haloalkoxy;
RS and R6 are independently selected from phenyl, 2-alkoxyphenyl, 3-
alkoxyphenyl,
2-halophenyl, 2-alkylphenyl, 2-haloalkylphenyl, 2-haloalkoxyphenyl, furan-2-
yl, thiophen-
3'-yl, or pyridin-4-yl;
R' and R$ are independently selected from phenyl, 2-alkoxyphenyl, 3-
alkoxyphenyl,
2-halophenyl, 2-alkylphenyl, 2-haloalkylphenyl, 2-haloalkoxyphenyl, furan-2-
yl, thiophen-
3-yl, or pyridin-4-yl; and
R9 is a branched alkyl chain of 4-6 carbon atoms or trifluoroalkoxy;
RZ is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl,
2-
propyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-ethylbutyl, thiazolylmethyl,
pyrazol-1-
~ ylmethyl, 1,2,3-triazol-1-ylmethyl, 1,2,4-triazol-1-ylmethyl, pyrrol-1-
ylmethyl, imidazol-1-
ylmethyl, tetrazol-1-ylmethyl, 2-methylpropyl, 2,4,4-trimethylpentyl, 4-
methylindol-3-
ylmethyl, 2-napth-1-ylpropyl, benzyloxymethyl, 1-phenylcyclopropylmethyl, 1-
. phenylcyclobutylmethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-
phenylpropyl,
2-.phenylbutyl (wherein the phenyl group in 1-phenylcyclopropylmethyl, 1-
20~ phenylcyclobutylmethyl, benzyloxymethyl, 2-phenylprop-2-enyl, 2-phenyl-2-
methylpropyl,
2-phenylpropyl, or 2-phenylbutyl is optionally substituted with one or two
substituents
independently selected from alkyl, halo, haloalkoxy, haloalkyl, or alkoxy),
benzyl (where
the phenyl ring in the benzyl group is substituted at the 2 and 6 positions
with groups
independently selected from alkyl, halo, haloalkyl, alkoxy or haloalkoxy and
at the 4
. position with hydrogen, alkyl, halo, haloalkyl, alkoxy, alkoxyalkyloxy,
aminoalkyloxy,
_ alkoxyalkylthio, aminoalkylthio, haloalkoxy, alkylthio, alkylsulfinyl,
alkylsulfonyl, cyano,
amino, alkylamino, or dialkylamino), heteroaryl(C3_6)alkyl and 1-
heteroaryl(C3_6)-
cycloalkylmethyl and furthermore wherein the alkyl chain in the above groups
is optionally
substituted with one to six halo;
. RZa is hydrogen or R2a and RZ together with the carbon atom to which they
are
attached form cyclohexyl or cycloheptyl;
. R3 is ethyl, propyl, or n-butyl;
R4 is benzoxazol-2-yl, oxazolo[4,5-b]pyridin-2-yl, 2-pyridin-3-yl-[1,3,5]-
oxadiazol-
5-yl, 2-pyridin-4-yl-[1,3,4]-oxadiazol-5-yl, 2-ethyl-[1,3,4]-oxadiazol-5-yl, 2-
phenyl-[1,3,4]-
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oxadiazol-5-yl, pyrazin-2-yl, pyrimidin-2-yl, pyridazin-3-yl, 3-phenyl-[1,2,4]-
oxadiazol-5-
yl, or 3-ethyl-[1,2,4-oxadiazol-S-yl;
Rl° is hydrogen, hydroxy, alkoxy; and
Ri l is hydroxy or alkoxy; or
, Rl° and Rl 1 together with the carbon atom to which they are attached
form (=O) or
-O-(CZ-C4)alkylene-O- wherein the alkylene chain is optionally substituted
with one or two
' alkyl; or a pharmaceutically acceptable salt thereof.
Preferably, the compound of Formula I is represent by Formula Ia:
O Rz R~° R~~
R~~N~N~R4
H IOI R3
Ia
v~herein:
R1 is a group of formula:
(i)
Y X
\ / za_~~~-;
(ii)
Xa
_ c
\ /
Z
Xb
(111)
, . Xa
\ / \ / ~_
Xb ,
(1V)
X \
Y
.. ;
(v)
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Xa
,
Xb
. (V1)
, . Xa
i
. (V11)
Xa
Q
. . . Xb ,
(Vlll)
.. X
. Q ~t~
,.
(i~c)
R5
10~ Rs
.. (x)
R$
,
.. ., ~Q
R ;
(xi)
Rs ~ ~ ~_
. (Xii) 1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)pyrazol-3-yl;
. _ (xiii) 1-methyl-3-trifluoro-1H-thieno-[2,3-c]-pyrazol-5-yl;
(xiv)
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H02C~ Z°~
\ / Za_Zb ~ .
Xa i
(XV)
HOZC~ -
\ / \ / ~_
Y
,
(xvi)
Y
H02C~ Za-
\ / \ / ~_
r
(XVll)
COOH
H02C~ Za-
\ / \ / ~_
x
- (xviii)
R$
Q
i
~ (xix)
Y X
,.. \ N \
. (xx) 4-(3,5-dimethyloxazol-4-yl)phenyl; or
(xxi) 4-(5-carboxy-2-methylthiophen-3-yl)phenyl;
~ where:
Za, Zb, and Z° are independently selected from -CH- or N- provided that
if an Rl
group contains Za, Zb, and Z° simultaneously then, when Z° is N-
, then Za is N- or -CH-
and Zb is -CH-; and when Zb is N- then Za and Z° are -CH-; and if an Rl
group contains
Za and Zb simultaneously, then both Za and Zb cannot simultaneously be N-;
' Q is NR- where R is hydrogen or alkyl, -O-, or -S-;
Q' is -CH- or N-;
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X and Y are independently selected from hydrogen, halo, alkyl, alkoxy,
haloalkyl, or
haloalkoxy provided that both X and Y are not simultaneously hydrogen;
Xa and Xb are independently selected from alkyl, halo, alkoxy, haloalkyl, or
haloalkoxy;
RS and R6 are independently selected from phenyl, 2-alkoxyphenyl, 3-
alkoxyphenyl,
2-halophenyl, 2-alkylphenyl, 2-haloalkoxyphenyl, furan-2-yl, thiophen-3-yl, or
pyridin-4-yl;
R~ and R$ are independently selected from phenyl, 2-alkoxyphenyl, 3-
alkoxyphenyl,
2-halophenyl, 2-alkylphenyl, 2-haloalkoxyphenyl, furan-2-yl, thiophen-3-yl, or
pyridin-4-yl;
and
~ R9 is a branched alkyl chain of 4-6 carbon atoms or trifluoroalkoxy;
RZ is selected from the group consisting of cyclopentyl, cyclohexyl,
cycloheptyl, 2-
' ethylbutyl, thiazolylmethyl, pyrazol-1-ylmethyl, 1,2,3-triazol-1-ylmethyl,
1,2,4-triazol-1-
ylmethyl, pyrrol-1-ylmethyl, imidazol-1-ylmethyl, tetrazol-1-ylmethyl, 2-
methylpropyl,
2,4,4-trimethylpentyl, 4-methylindol-3-ylmethyl, 2-napth-1-ylpropyl,
benzyloxymethyl, 1-
~ phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, 2-phenylprop-2-enyl, 2-
phenyl-2-
methylpropyl, 2-phenylpropyl, 2-phenylbutyl wherein the phenyl group in 1-
phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, benzyloxymethyl, 2-
phenylprop-2-
eriyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, or 2-phenylbutyl is optionally
substituted
with one or two substituents independently selected from alkyl, halo,
haloalkoxy, haloalkyl,
or alkoxy, and benzyl where the phenyl ring in the benzyl group is substituted
at the 2 and 6
positions with groups independently selected from alkyl, halo, haloalkyl,
alkoxy or
haloalkoxy and at the 4 position with hydrogen, alkyl, halo, haloalkyl,
alkoxy,
alkoxyalkyloxy, aminoalkyloxy, alkoxyalkylthio, aminoalkylthio, haloalkoxy,
alkylthio,
. alkylsulfmyl, alkylsulfonyl, cyano, amino, alkylamino, or dialkylamino;
~ , R3 is ethyl, propyl, or n-butyl;
R4 is benzoxazol-2-yl, oxazolo[4,5-b]pyridin-2-yl, 2-pyridin-3-yl-[1,3,5]-
oxadiazol-
5-yl, 2-pyridin-4-yl-[1,3,4]-oxadiazol-5-yl, 2-ethyl-[1,3,4]-oxadiazol-5-yl, 2-
phenyl-[1,3,4]-
oxadiazol-5-yl, pyrazin-2-yl, pyrimidin-2-yl, pyridazin-3-yl, 3-phenyl-[1,2,4]-
oxadiazol-5-
y~, or 3-ethyl-[1,2,4]-oxadiazol-5-yl;
30~ Rl° is hydrogen, hydroxy, alkoxy; and
Rl i is hydroxy or alkoxy; or
Rl° and Rl l together with the carbon atom to which they are attached
form (=O) or
-O-(CZ-C4)alkylene-O- wherein the alkylene chain is optionally substituted
with one or two
alkyl; or a pharmaceutically acceptable salt thereof.
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. ' More preferably, a compound of Formula Ia wherein Rl is a group of
formula:
(i)
Y X
. \ / \ / ~-;
(ii)
. Xa
\ / \ / ~_
5. Xb
(111)
Xa
.~ \ / \ / ~-
Xb
(1V)
X \ / ~-
\ Y ,
- , / ;
. . (V)
Xa \
. Xb
..
;
Xa
' ~ Q
\ /
. (Vll)
Xa
.. \ /
Xb
' (ylll)
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' X
. . Q
~ ~.
Y
. , (ix)
R5
_.
_ , R6
(x)
R$
R ;
(xi)
Rs
(xii) 1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)pyrazol-3-yl; or
(xiii) 1-methyl-3-trifluoro-1H-thieno-[2,3-c]-pyrazol-4-yl;
where:
Q is NR- where R is hydrogen or alkyl, -O-, or -S-;
Q' is -CH- or N-;
X and Y are independently selected from hydrogen, halo, alkyl, alkoxy, or
haloalkoxy provided that both X and Y are not simultaneously hydrogen;
15' ~ Xa and Xb are independently selected from alkyl, halo, alkoxy, or
haloalkoxy; and
R2 is selected from the group consisting of cyclopentyl, cyclohexyl, 2-
methylpropyl,
2,4,4-trimethylpentyl, 4-methylindol-3-ylmethyl, 2-napth-1-ylpropyl,
benzyloxymethyl, 2-
phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-phenylbutyl
wherein the
' phenyl group in benzyloxymethyl, 2-phenylprop-2-enyl, 2-phenyl-2-
methylpropyl, 2
20v phenylpropyl, or 2-phenylbutyl is optionally substituted with one or two
substituents
- independently selected from alkyl, halo, haloalkoxy, or alkoxy, and benzyl
where the
phenyl ring is substituted with two halo groups;
R3 is ethyl, propyl, or fa-butyl;
R4 is benzoxazol-2-yl, oxazolo-[4,5-b]-pyridin-2-yl, 2-pyridin-3-yl-[1,3,5]-
25-~ oxadiazol-5-yl, 2-pyridin-4-yl-[1,3,4]-oxadiazol-5-yl, 2-ethyl-[1,3,4]-
oxadiazol-5-yl, 2-
. ~ phenyl-[1,3,4]-oxadiazol-5-yl, imidazol-2-yl, pyridazin-3-yl, 3-phenyl-
[1,2,4]-oxadiazol-5-
yi, or 3-ethyl-[1,2,4)-oxadiazol-5-yl;
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Rl° and Rl1 together with the carbon atom to which they are attached
form (=O); and
other groups are as defined in Formula Ia above.
In a second aspect, this invention is directed to a pharmaceutical composition
comprising a compound of Formula I or Ia or a pharmaceutical acceptable salt
thereof and a
5. ~ pharmaceutically acceptable excipient.
In a third aspect, this invention is directed to a method of treating a
disease in a
patient mediated by cathepsins B, K, L, F, and/or S which method comprises
administering
' to said patient a pharmaceutical composition comprising a compound of
Formula I or Ia or a
pharmaceutical acceptable salt thereof and a pharmaceutically acceptable
excipient.
Preferably the disease is Alzheimer's disease, respiratory disease such as
asthma,
osteoporosis, atherosclerosis, restenosis, and autoimmune diseases such as
rheumatoid
. arthritis, systemic lupus erythematosus, Crohn's disease, ulcerative
colitis, multiple
_ sclerosis, Guillain-Barre Syndrome, psoriasis, Grave's disease, myasthenia
gravis,
scleroderma, glomrulonenephritis, dermatitis, endometriosis or insulin
dependent diabetes
~ mellitus.
In a fourth aspect, this invention is directed to an intermediate of formula
II:
R2
R2°HN~COOR~~
wherein:
R2 is selected from the group consisting of cyclopentyl, cyclohexyl,
cycloheptyl, 2-
~ ethylbutyl, thiazolylmethyl, pyrazol-1-ylmethyl, 1,2,3-triazol-1-ylmethyl,
1,2,4-triazol-1
. ~ ylmethyl, pyrrol-1-ylmethyl, imidazol-1-ylmethyl, tetrazol-1-ylmethyl, 2-
methylpropyl,
x;4,4-trimethylpentyl, 4-methylindol-3-ylmethyl, 2-napth-1-ylpropyl,
benzyloxymethyl, 1-
. phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, 2-phenylprop-2-enyl, 2-
phenyl-2-
methylpropyl, 2-phenylpropyl, 2-phenylbutyl (wherein the phenyl group in 1-
.. phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, benzyloxymethyl, 2-
phenylprop-2-
enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, or 2-phenylbutyl is optionally
substituted
with one or two substituents independently selected from alkyl, halo,
haloalkoxy, haloalkyl,
. ~ or alkoxy), benzyl (where the phenyl ring in the benzyl group is
substituted at the 2 and 6
positions with groups independently selected, from alkyl, halo, haloalkyl,
alkoxy or
. ~ haloalkoxy and at the 4 position with hydrogen, alkyl, halo, haloalkyl,
alkoxy,
alkoxyalkyloxy, aminoalkyloxy, alkoxyalkylthio, aminoalkylthio, haloalkoxy,
alkylthio,
alkylsulfinyl, .alkylsulfonyl, cyano, amino, alkylamino, or dialkylamino),
heteroaryl(C3_
'' 6)alkyl and 1-heteroaryl(C3_6)cycloalkylmethyl and furthermore wherein the
alkyl chain in
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the above groups is optionally substituted with one to six halo. Preferably,
RZ is selected
from the group consisting of cycloheptyl, 2-ethylbutyl, thiazolylmethyl,
pyrazol-1-ylmethyl,
1,2,3-triazol-1-ylmethyl, 1,2,4-triazol-1-ylmethyl, pyrrol-1-ylmethyl,
imidazol-1-ylmethyl,
tetrazol-1-ylrnethyl, 2-methylpropyl, 2,4,4-trimethylpentyl, 4-methylindol-3-
ylmethyl, 2-
napth-1-ylpropyl, benzyloxymethyl, 1-phenylcyclopropylmethyl, 1-
phenylcyclobutylmethyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-
phenylpropyl,
. . 2-phenylbutyl wherein the phenyl group in 1-phenylcyclopropylmethyl, 1-
phenylcyclobutylmethyl, benzyloxymethyl, 2-phenylprop-2-enyl, 2-phenyl-2-
methylpropyl, 2-phenylpropyl, or 2-phenylbutyl is optionally substituted with
one or two
substituents independently selected from alkyl, halo, haloalkoxy, haloalkyl,
or alkoxy, and
benzyl where the phenyl ring in the benzyl group is substituted at the 2 and 6
positions with
,groups independently selected from alkyl, halo, haloalkyl, alkoxy or
haloalkoxy and at the 4
position with hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, alkylthio,
alkylsulfinyl,
. alkylsulfonyl, cyano, amino, alkylamino, or dialkylamino;
. ~ R2° is an amino-protecting group or hydrogen; preferably tert-
butoxycarbonyl or
benzyloxycarbonyl; and
R21 is a carboxy-protecting group or hydrogen.
DETAILED DESCRIPTION OF THE INVENTION
~ Definitions:
Unless otherwise stated, the following terms used in the specification and
claims are
defined for the purposes of this Application and have the following meanings:
.' "Alkyl" means a linear saturated monovalent hydrocarbon radical of one to
six
carbon atoms or a branched saturated monovalent hydrocarbon radical of three
to six carbon
atoms, e.g., methyl, ethyl, propyl, 2-propyl, butyl (including all isomeric
forms), pentyl
(including all isomeric forms), and the like.
"Alkylene" means a linear saturated divalent hydrocarbon radical of one to six
carbon
-~ atoms unless otherwise stated, e.g., (C2~)alkylene includes, but is not
limited to, groups such
.as ethylene, propylene, 2-propylene, and butylene.
~ ~ "Alkoxy" means a radical -OR where R is alkyl as defined above, e.g.,
methoxy,
ethoxy, propoxy, or 2-propoxy, fa-, iso-, or test-butoxy, and the like,
preferably methoxy.
"Alkoxyalkyloxy" means a radical -0-(alkylene)OR where R is alkyl as defined
above, e.g., methoxymethyloxy, ethoxymethyloxy, 2-methoxyethyloxy, or 2-
propoxyethyloxy, and the like.
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"Alkoxyalkylthio" means a radical -S-(alkylene)OR where R is alkyl as defined
above, e.g., methoxymethylthio, ethoxymethylthio, 2-methoxyethylthio, or 2-
propoxyethylthio, and the like.
"Aminoalkyloxy" means a radical -O-(alkylene)NRR' where R and R' are
independently hydrogen or alkyl as defined above, e.g., methylaminoethyloxy,
dimethylaminoethyloxy, and the like.
"Aminoalkylthio" means a radical -S-(alkylene)NRR' where R and R' are
independently hydrogen or alkyl as defined above, e.g., methylaminoethylthio,
dimethylaminoethylthio, and the like.
"Alkylthio" means a radical -SR where R is alkyl as defined above, e.g.,
methylthio,
ethylthio, and the like.
"Alkylsulfinyl" means a radical -S(O)R where R is alkyl as defined above,
e.g.,
methylsulfinyl, ethylsulfinyl, and the like.
"Alkylsulfonyl" means a radical -S(O)ZR where R is alkyl as defined above,
e.g.,
15. methylsulfonyl, ethylsulfonyl, and the like.
"Alkylamino" means a radical NHR where R is alkyl as defined above, e.g.,
methylamino, ethylamino, and the like.
"Cycloalkyl" means a cyclic monovalent saturated monovalent hydrocarbon
radical
of three to six carbon atoms unless otherwise indicated e.g., cyclopropyl,
cyclobutyl, and
, ~ the like, preferably cyclopropyl.
"Dialkylamino" means a radical NRR' where R and R' are independently alkyl as
defined above, e.g., dimethylamino, methylethylamino, and the like.
"Halo" means fluoro, chloro, bromo, and iodo, preferably fluoro or chloro.
"Haloalkyl" means alkyl substituted with one or more halogen atoms, preferably
one
~ to three halogen atoms, preferably fluorine or chlorine, including those
substituted with
' , different halogens, e.g., -CHZCI, -CF3, -CHFZ, and the like, preferably
trifluoromethyl.
"Haloalkoxy" means a radical -OR where R is haloalkyl as defined above, e.g.,
trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, and the like,
preferably
trifluoromethoxy.
"Heteroaryl" means a monovalent monocyclic or bicyclic aromatic radical of 5
to 10
. ~ ~ ring atoms containing one or more, preferably one or two ring
heteroatoms selected from N,
.~ O, or S, the remaining ring atoms being carbon. The heteroaryl ring is
optionally substituted
,~' with one or more substituents, preferably one or two substituents,
independently selected
.from alkyl, haloalkyl, alkoxy, alkylthio, halo, nitro, cyano, amino, alkyl or
dialkylamino,
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liydroxy, carboxy, or -COOR where R is alkyl as define above. More
specifically the term
~. . heteroaryl includes, but is not limited to, pyridyl, pyrrolyl,
imidazolyl, thienyl, furanyl,
indolyl, quinolyl, pyrazine, pyrimidine, pyradizine, oxazole, isooxazolyl,
benzoxazole,
quinoline, isoquinoline, benzopyranyl, thiazolyl, and the like.
5, ~ "Heteroaryl(C3_6)alkyl" means an alkylene chain of three to six carbon
atoms
carrying a heteroaryl group as defined above.
"1-Heteroaryl(C3_6)cycloalkylmethyl" means a radial of the formula:
where R is a heteroaryl group as defined above and n is l, 2, 3 or 4.
Representative examples include, but are not limited to, 1-pyridin-2-
ylcyclopropylmethyl,
. 1-pyridin-2-ylcyclobutylmethyl, and the like.
The present invention also includes the prodrugs of compounds of Formula I.
The
term prodrug is intended to represent covalently bonded carriers, which are
capable of
releasing the active ingredient of Formula I when the prodrug is administered
to a
mammalian subject. Release of the active ingredient occurs ih vivo. Prodrugs
can be
. prepared by techniques known to one skilled in the art. These techniques
generally modify
appropriate functional groups in a given compound. These modified functional
groups
however regenerate original functional groups by routine manipulation or in
vivo. Prodrugs
of compounds of Formula I are also within the scope of this invention.
The present invention also includes N-oxide derivatives and protected
derivatives of
. compounds of Formula I. For example, when compounds of Formula I contain an
oxidizable nitrogen atom, the nitrogen atom can be converted to an N-oxide by
methods well
known in the art or ih vivo. For example, the nitrogen atom in a pyridyl group
in a
compound of Formula I can be oxidized to give a corresponding pyridyl-N-oxide
c~mpound
of Formula I.
25~ ~ ~ . A "pharmaceutically acceptable salt" of a compound means a salt that
is
pharmaceutically acceptable and that possesses the desired pharmacological
activity of the
parent compound. Such salts include:
acid addition salts, formed with inorganic acids such as hydrochloric acid,
hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like;
or formed with
organic acids such as acetic acid, propionic acid, hexanoic acid,
cyclopentanepropionic acid,
~glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic
acid, malefic acid,
Attorney Docket No. 1051-PCT 15
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fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-
hydroxybenzoyl)benzoic acid,
cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-
ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-
chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic
acid,
>~ camphorsulfonic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-
ene-1-carboxylic
acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic
acid, lauryl sulfuric
acid, gluconic acid, glutarnic acid, hydroxynaphthoic acid, salicylic acid,
stearic acid,
muconic acid, and the like; or
salts formed when an acidic proton present in the parent compound either is
replaced
10. by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an
aluminum ion; or
coordinates with an organic base such as ethanolamine, diethanolamine,
triethanolamine,
. tromethamine, N methylglucamine, and the like. It is understood that the
pharmaceutically
acceptable salts are non-toxic. Additional information on suitable
pharmaceutically
', acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th
ed., Mack
1 ~ Publishing Company, Easton, PA, 1985, which is incorporated herein by
reference.
The compounds of the present invention may have asymmetric centers. Compounds
of the present invention containing an asymmetrically substituted atom may be
isolated in
optically active or racemic forms. It is well known in the art how to prepare
optically active
forms, such as by resolution of materials. All enantiomeric, diastereomeric,
and racemic
20. ~ forms are within the scope of this invention, unless the specific
stereochemistry or isomeric
form is specifically indicated.
Additionally, as used herein the terms alkyl includes all the possible
isomeric forms
of said alkyl group albeit only a few examples are set forth.
"Optional" or "optionally" means that the subsequently described event or
25.~ circumstance may but need not occur, and that the description, includes
instances where the
event or circumstance occurs and instances in which it does not. For example,
the term
v "phenyl group optionally with an alkyl group" means that the alkyl may but
need not be
,present, and the description includes situations where the phenyl group is
substituted with an
alkyl group and situations where the phenyl group is not substituted with the
alkyl group.
30 " A "pharmaceutically acceptable carrier or excipient" means a carrier or
an excipient
_ that is useful in preparing a pharmaceutical composition that is generally
safe, non-toxic and
neither biologically nor otherwise undesirable, and includes a carrier or an
excipient that is
acceptable for veterinary use as well as human pharmaceutical use. "A
pharmaceutically
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acceptable carner/excipient" as used in the specification and claims includes
both one and
more than one such excipient.
"Treating" or "treatment" of a disease includes:
(1) preventing the disease, i.e. causing the clinical symptoms of the disease
not to
. develop in a mammal that may be exposed to or predisposed to the disease but
does not yet experience or display symptoms of the disease;
(2) inhibiting the disease, i.e., arresting or reducing the development of the
disease or
its clinical symptoms; or
(3) relieving the disease, i.e., causing regression of the disease or its
clinical
10~ symptoms.
A "therapeutically effective amount" means the amount of a compound of Formula
I
that, when administered to a mammal for treating a disease, is sufficient to
effect such
. treatment for the disease. The "therapeutically effective amount" will vary
depending on the
compound, the disease and its severity and the age, weight, etc., of the
mammal to be
treated.
Preferred Embodiments
While the broadest definition of this invention is set forth in the Summary of
the
- Invention, certain compounds of Formula I are preferred. For example:
20. ~ 1. A preferred group of compounds of Formula I is represented by Formula
Ib:
R2 H O
R~ H~N~Ra
O TR
Ib
is that wherein:
Rl is a group of formula:
. (i)
Y X
~a-Zb
(11)
Xa
Z~
Za-Zb ~_
Xb
. ~ (111)
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Xa
\ / \ ~
r
~ Xb
(1V)
X \
Y
i
. (v)
Xa \
Xb
,
(V1)
.. Xa
lO (V11)
Xa
Q
.. \ ~ \ I
Xb
(V111)
X
C~
.. . \ l \ I ;
Y
(ix)
R5
, . . \-~ ~_
~ ~ ~ R6
(~)
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R$
R ;
(xi)
R9 ~ ~ ~_
(xii) 1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)pyrazol-3-yl; or
(xiii) 1-methyl-3-trifluoro-1H-thieno-[2,3-c]-pyrazol-4-yl;
wherein:
Za, Zb and Z° are -CH-;
Q is NR- where R is hydrogen or alkyl, -O-, or -S-;
Q' is -CH- or N-;
X and Y are independently selected from hydrogen, chloro, methyl, methoxy,
trifluoromethyl, or trifluoromethoxy;
Xa, and Xb are independently selected from methyl, chloro, fluoro, methoxy,
trifluoromethyl, or trifluoromethoxy;
RS and R6 are independently selected from phenyl, 2-alkoxyphenyl, 3-
alkoxyphenyl,
. . 2-halophenyl, 2-alkylphenyl, 2-haloalkoxyphenyl, furan-2-yl, thiophen-3-
yl, or pyridin-4-yl;
R~ and R8 are independently selected from phenyl, 2-alkoxyphenyl, 3-
alkoxyphenyl,
2-halophenyl, 2-alkylphenyl, 2-haloalkoxyphenyl, furan-2-yl, thiophen-3-yl, or
pyridin-4-yl;
RZ is selected from the group consisting of cyclopentyl, cyclohexyl,
cycloheptyl, 2-
- ethylbutyl, thiazol-2-ylmethyl, pyrazol-1-ylmethyl, 1,2,3-triazol-1-
ylmethyl, 1,2,4-triazol-1-
.. ylmethyl, pyrrol-1-ylmethyl, imidazol-1-ylmethyl, tetrazol-1-ylmethyl, 2-
methylpropyl,
2,4,4-trimethylpentyl, 4-methylindol-3-ylmethyl, 2-napth-1-ylpropyl,
benzyloxymethyl, 1-
_ phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, 2-phenylprop-2-enyl, 2-
phenyl-2-
methylpropyl, 2-phenylpropyl, 2-phenylbutyl (wherein the phenyl group in 1-
phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, benzyloxymethyl, 2-
phenylprop-2-
~ enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, or 2-phenylbutyl is
optionally substituted
. with one or two substituents independently selected from alkyl, halo,
haloalkoxy, haloalkyl,
. ~ , or alkoxy) and benzyl (where the phenyl ring in the benzyl group is
substituted at the 2 and
6 positions with groups independently selected from alkyl, halo, haloalkyl,
alkoxy or
haloalkoxy and at the 4 position with hydrogen, alkyl, halo, haloalkyl,
alkoxy,
~alkoxyalkyloxy, aminoalkyloxy, alkoxyalkylthio, aminoalkylthio, haloalkoxy,
alkylthio,
alkylsulfinyl, alkylsulfonyl, cyano, amino, alkylamino, or dialkylamino,
preferably the
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phenyl ring in the benzyl group is substituted at the 2 and 6 positions with
groups
independently selected from methyl, chloro, fluoro, trifluoromethyl, methoxy,
' ~ trifluoromethoxy, or difluoromethoxy and at the 4 position with hydrogen,
methyl, ethyl,
propyl, chloro, fluoro, trifluoromethyl, methoxy, 2-methoxyethyloxy, 2-
~ dimethylaminoethyloxy, trifluorornethoxy, difluorornethoxy, methylthio,
methylsulfinyl,
methylsulfonyl, cyano, amino, methylamino or dimethylamino). RZ is preferably
selected
from the group consisting of cyclohexyl, cycloheptyl, thiazol-2-ylmethyl, 2-
ethylbutyl,
pyrazol-1-ylmethyl, 2-methylpropyl, 2,4,4-trimethylpentyl, 2-napth-1-ylpropyl,
2-
phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-(2-
methoxyphenyl)propyl,
4-methylindol-3-ylmethyl, 2-(2,5-dimethylphenyl)propyl, benzyloxymethyl, 2-
(2,4-
dirnethylphenyl)propyl, 2-(2,4-dichlorophenyl)-propyl, 2,6-difluorobenzyl, 2,5-
. difluorobenzyl, and 2,3-difluorobenzyl;
R4 is benzoxazol-2-yl, oxazolo[4,5-b]pyridin-2-yl, 2-pyridin-3-yl-[1,3,5]-
oxadiazol
,~~ 5-yl, 2-pyridin-4-yl-[1,3,4]-oxadiazol-5-yl, 2-ethyl-[1,3,4]-oxadiazol-S-
yl, 2-phenyl-[1,3,4]
15. oxadiazol-5-yl, pyrazin-2-yl, pyrimidin-2-yl, pyridazin-3-yl, 3-phenyl-
[1,2,4]-oxadiazol-5
yl, or 3-ethyl-[1,2,4]-oxadiazol-5-yl and R9 is as defined in the Summary of
the Invention.
With the above group, a more preferred group of compounds is that wherein:
X and Y are independently selected from hydrogen, chloro, methyl, methoxy, or
trifluoromethoxy, preferably hydrogen, chloro, methyl, or methoxy;
, X$, and Xb are independently selected from methyl, chloro, fluoro, methoxy,
or
trifluoromethoxy, preferably chloro, methyl, or methoxy;
' R2 is selected from the group consisting of 2-methylpropyl, 2,4,4-
trimethylpentyl, 2-
napth-1-ylpropyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-
phenylpropyl, 2-(2-
methoxy-phenyl)propyl, 4-methylindol-3-ylmethyl, 2-(2,5-dimethylphenyl)propyl,
~ benzyloxymethyl, 2-(2,4-dimethylphenyl)propyl, 2-(2,4-dichlorophenyl)propyl,
2,6-
difluorobenzyl, 2,5-difluorobenzyl, and 2,3-difluorobenzyl; preferably 2,6-
difluorobenzyl or
_ 2S-phenylpropyl and the stereochemistry at the carbon atom to which R2 is
attached is (S~
when the Prelog rule places the order of the substituent 1) N, 2) -COON, 3) R2
and 4) H;
and (R) when the Prelog rule places the order of the substituent 1) N, 2) RZ,
3) --COOH and
30=I 4) H;
R4 is benzoxazol-2-yl, oxazolo[4,5-b]pyridin-2-yl, 2-pyridin-3-yl-[1,3,5]-
oxadiazol
' ,5-yl, 2-pyridin-4-yl-[1,3,4]-oxadiazol-5-yl, 2-ethyl-[1,3,4]-oxadiazol-5-
yl, 2-phenyl-[1,3,4]
oxadiazol-5-yl, pyridazin-3-yl, 3-phenyl-[1,2,4]-oxadiazol-5-yl, or 3-ethyl-
[1,2,4]
. . oxadiazol-5-yl; and
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the stereochemistry at the carbon atom to which R3 is attached is (~.
Within the above preferred and more preferred groups, an even more preferred
group of compounds is that wherein Rl is 2'-chlorobiphen-4-yl, 2',3-
dichlorobiphenyl-4-yl,
2',6'-dichlorobiphen-4-yl, 2',6'-dimethylbiphen-4-yl, 2'-methylbiphen-4-yl, 2'-
. fluorobiphen-4-yl; 4-trifluoromethoxyphenyl, 4-(2-butyl)phenyl, 3,5-
diphenylphenyl, 2,3-
diphenylthiophen-5-yl, 2-(2-methylphenyl)furan-5-yl, 2-(2-methoxyphenyl)furan-
5-yl, 3-
methoxy-2-(2-methylphenyl)thiophen-4-yl, 3-methoxy-2-(2-methoxyphenyl)thiophen-
4-yl,
2,3-di(2-methoxyphenyl)thiophen-5-yl, 3,5-di(2-methoxyphenyl)phenyl, 3,5-di(3-
rriethoxyphenyl-phenyl, 3,5-di(thiophen-3-yl)phenyl, 3,5-di(pyridin-4-
yl)phenyl, 2,3-di(2-
. methylphenyl)-thiophen-5-yl, 4-test-butylphenyl, 2,3-di(furan-2-yl)thiophen-
5-yl, 3,5-
di(furan-2-yl)phenyl, 4-(2-methylphenyl)thiophen-2-yl, 4-(2-
methoxyphenyl)thiophen-2-yl,
2'-chlorobiphen-3-yl, 2'-methyl-4-chlorobiphenyl-3-yl, 3,5-di(2-
chlorophenyl)phenyl, 2,3-
di(2-chlorophenyl)thiophen-5-yl, 1-(4-aminosulfonylphenyl)-5-(4-
chlorophenyl)pyrazol-3-
- ' yl, 2-(2,6-dichlorophenyl)furan-5-yl, 2,3-diphenylthiophen-5-yl, 4,5-
diphenylthiazol-2-yl,
15~ 3-trifluoromethyl-1-methylthieno[2,3-c]pyrazol-5-yl, 3-methylbiphen-4-yl,
2'-
methoxybiphen-4-yl, 2,'-trifluoromethylbiphen-4-yl, or 2'-methyl-3-
chlorobiphen-4-yl.
More preferably, RI is 2'-chlorobiphen-4-yl, 2',3-dichlorobiphenyl-4-yl, 2',6'-
dichlorobiphen-4-yl, 2',6'-dimethylbiphen-4-yl, 2'-methylbiphen-4-yl, 2'-
fluorobiphen-4-
yl; 4-trifluoromethoxy-phenyl, 4-(2-butyl)phenyl, 3,5-diphenylphenyl, 2,3-
diphenylthiophen-5-yl, 2-(2-methylphenyl)-furan-5-yl, 2-(2-methoxyphenyl)furan-
5-yl, 3-
methoxy-2-(2-methylphenyl)thiophen-4-yl, 3-methoxy-2-(2-methoxyphenyl)thiophen-
4-yl,
. .2,3-di(2-methoxyphenyl)thiophen-5-yl, 3,5-di(2-methoxyphenyl)phenyl, 3,5-
di(3-
methoxyphenyl)phenyl, 3,5-di(thiophen-3-yl)phenyl, 3,5-di(pyridin-4-yl)phenyl,
2,3-di(2-
.~ methylphenyl)thiophen-5-yl, 4-tent-butylphenyl, 2,3-di(furan-2-yl)thiophen-
5-yl, 3,5-
~ di(furan-2-yl)phenyl, 4-(2-methylphenyl)thiophen-2-yl, 4-(2-methoxyphenyl)-
thiophen-2
= y~, 2'-chlorobiphen-3-yl, 2'-methyl-4-chlorobiphenyl-3-yl, 3,5-di(2-
chlorophenyl)-phenyl,
2,3-di(2-chlorophenyl)thiophen-5-yl, 1-(4-aminosulfonylphenyl)-5-(4-
chlorophenyl)
. . , pyrazol-3-yl, 2-(2,6-dichlorophenyl)furan-5-yl, 2,3-diphenylthiophen-5-
yl, 4,5-
diphenylthiazol-2-yl, or 3-trifluoromethyl-1-methylthieno[2,3-c]pyrazol-5-yl.
Even more
30v, preferably, Rl is 2'-chlorobiphen-4-yl, 2',6'-dichlorobiphen-4-yl or 2',3-
dichlorobiphen-4-
yl.
Within these preferred and more preferred groups, a particularly preferred
group of
compounds is that wherein R3 is ethyl.
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Within these preferred, more preferred groups, and particularly preferred
groups, a
more particularly preferred group of compounds is that wherein R4 is
benzoxazol-2-yl.
2': Another preferred group of compounds of Formula I is represented by
Formula
Ic:
RZ H O
R~ H~N~Ra
IOI
Ic
is that wherein:
Rl is a group of formula:
w Y X
~ \ / za-Zb ~ a
' IZ
_ Xa
_ c
. ..... . \ / Za~~_
Z ,
Xb
(X1V)
H02C\ Z°~
\ / '
Za-~b
Xa
~, , (xv)
' X
:, H02C~ -
- \/ \/~_
Y
(xvi)
- Y
.. H02C
\ / \ / ~_
X
(xvii)
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COOH
H02C~ Za-
\ / \ / ~_
x
(xviii)
R8
Q
(xix)
Y X
5. . \ N \
(xx) 4-(3,5-dimethyloxazol-4-yl)phenyl; or
(xxi) 4-(5-carboxy-2-methylthiophen-3-yl)phenyl;
wherein:
Za, Zb, and Z° are independently selected from -CH- or N- provided that
when Rl is
a group of formula (i) then one of Z$ and Zb is N- and the other is -CH-; when
Rl is a
. . group of formula (ii), then Z~ is N-, Za is N- or -CH- and Zb is -CH-; or
Zb is N- and Za
and Z~ are -CH-; and when Rl is a group of formula (xiv), then when Z°
is N-, then Za is -
N- or -CH-, and Zb is -CH-; and when Zb is N-, then Za and Z~ are -CH-;
X and Y are independently selected from hydrogen, chloro, methyl, methoxy,
- trifluoromethyl, or trifluoromethoxy, preferably hydrogen, chloro, methyl,
methoxy, or
trifluoromethoxy, more preferably hydrogen, chloro, methyl, or methoxy;
X$, and Xb are independently selected from methyl, chloro, fluoro, methoxy,
trifluoromethyl, or trifluoromethoxy, preferably methyl, chloro, fluoro,
methoxy, or
txifluoromethoxy, more preferably chloro, methyl, or methoxy;
20~ ~ R$ is phenyl, 2-alkoxyphenyl, 3-alkoxyphenyl, 2-halophenyl, 2-
alkylphenyl, 2-
haloalkoxyphenyl, furan-2-yl, thiophen-3-yl, or pyridin-4-yl;
R2 is selected from the group consisting of cyclopentyl, cyclohexyl,
cycloheptyl, 2-
ethylbutyl, thiazolylmethyl, pyrazol-1-ylmethyl, 1,2,3-triazol-1-ylmethyl,
1,2,4-triazol-1-
ylmethyl, pyrrol-1-ylmethyl, imidazol-1-ylmethyl, tetrazol-1-ylmethyl, 2-
methylpropyl,
. 2;4,4-trimethylpentyl, 4-methylindol-3-ylmethyl, 2-napth-1-ylpropyl,
benzyloxymethyl, 1-
. _ phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, 2-phenylprop-2-enyl, 2-
phenyl-2-
methylpropyl, 2-phenylpropyl, 2-phenylbutyl (wherein the phenyl group in 1-
phenylcyclopropylmethyl, 1-phenylcyclobutylmethyl, benzyloxymethyl, 2-
phenylprop-2-
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enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, or 2-phenylbutyl is optionally
substituted
W with one or two substituents independently selected from alkyl, halo,
haloalkoxy, haloalkyl,
. . or alkoxy) and benzyl (where the phenyl ring in the benzyl group is
substituted at the 2 and
6 positions with groups independently selected from alkyl, halo, haloalkyl,
alkoxy or
.. haloalkoxy and at the 4 position with hydrogen, alkyl, halo, haloalkyl,
alkoxy,
alkoxyalkyloxy, aminoalkyloxy, alkoxyalkylthio, aminoalkylthio, haloalkoxy,
alkylthio,
. ~ alkylsulfinyl, alkylsulfonyl, cyano, amino, alkylamino, or dialkylamino,
preferably the
phenyl ring in the benzyl group is substituted at the 2 and 6 positions with
groups
independently selected from methyl, chloro, fluoro, trifluoromethyl, methoxy,
trifluoromethoxy, or difluoromethoxy and at the 4 position with hydrogen,
methyl, ethyl,
propyl, chloro, fluoro, trifluoromethyl, methoxy, 2-methoxyethyloxy, 2-
. dimethylaminoethyloxy, trifluoromethoxy, difluoromethoxy, methylthio,
methylsulfinyl,
methylsulfonyl, cyano, amino, methylamino or dimethylamino). RZ is preferably
selected
from the group consisting of cyclohexyl, cycloheptyl, thiazol-2-ylmethyl, 2-
ethylbutyl,
pyrazol-1-ylmethyl, 2-methylpropyl, 2,4,4-trimethylpentyl, 2-napth-1-ylpropyl,
2-
phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-(2-
methoxyphenyl)propyl,
4-methylindol-3-ylmethyl, 2-(2,5-dimethylphenyl)propyl, benzyloxymethyl, 2-
(2,4-
dimethyl-phenyl)propyl, 2-(2,4-dichlorophenyl)propyl, 2,6-difluorobenzyl, 2,5-
' . difluorobenzyl, and 2,3-difluorobenzyl; even more preferably 2-
methylpropyl, 2,4,4-
. trimethylpentyl, 2-napth-1-yl-propyl, 2-phenylprop-2-enyl, 2-phenyl-2-
methylpropyl, 2-
phenylpropyl, 2-(2-methoxyphenyl)propyl, 4-methylindol-3-ylmethyl, 2-(2,5-
dimethylphenyl)propyl, benzyloxymethyl, 2-(2,4-dimethyl-phenyl)propyl, 2-(2,4-
dichlorophenyl)propyl, 2,6-difluorobenzyl, 2,5-difluorobenzyl, and 2,3-
difluorobenzyl;
~ ~ ' particularly preferably RZ is 2,6-difluorobenzyl or 2S-phenylpropyl and
the stereochemistry
25- at the carbon to which RZ is attached is (S) when the Prelog rule places
the order of the
substituent 1) N, 2) --COOH, 3) RZ and 4) H; and (R) when the Prelog rule
places the order
of the substituent 1) N, 2) R2, 3) -COOH and 4) H;
R4 is benzoxazol-2-yl, oxazolo[4,5-b]pyridin-2-yl, 2-pyridin-3-yl-[1,3,5]-
oxadiazol-
_~ 5-yl, 2-pyridin-4-yl-[1,3,4]-oxadiazol-5-yl, 2-ethyl-[1,3,4]-oxadiazol-5-
yl, 2-phenyl-[1,3,4]-
dxadiazol-5-yl, pyrazin-2-yl, pyrimidin-2-yl, pyridazin-3-yl, 3-phenyl-[1,2,4]-
oxadiazol-5-
yl, or 3-ethyl-[1,2,4]-oxadiazol-5-yl; and
the stereochemistry at the carbon atom to which R3 is attached is (S).
Within the above preferred and more preferred groups, an even more preferred
group of compounds is that wherein Rl is 2-(2-chlorophenyl)pyridin-5-yl, 2-
(2,6-
Attorney Docket No. 1051-PCT 24
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' dichlorophenyl)pyridin-5-yl, 2-(2-trifluoromethylphenyl)pyridin-5-yl, 4-(3-
methylpyridin-
2-yl)phenyl, 2-(2-chlorophenyl)-3-chloropyridin-5-yl, 4'-carboxy-2'-
chlorobiphen-4-yl, 4'-
carboxy-2'-fluorobiphen-4-yl, 4'-carboxy-2'-methylbiphen-4-yl, 5'-carboxy-2'-
methylbiphen-4-yl, 4-(3-methylpyridin-2-yl)phenyl, 5'-carboxy-2'-chlorobiphen-
4-yl, 2-(4-
carboxy-2-chlorophenyl)pyridin-5-yl, 2-(5-carboxy-2-chlorophenyl)pyridin-5-yl,
4-(5-
carboxy-2-methylthiophen-3-yl)phenyl, or 4-(3-methoxy-phenyl)thiophen-2-yl.
More
preferably Rl is 2-(2-chlorophenyl)pyridin-5-yl.
Within these preferred and more preferred groups, a particularly preferred
group of
' compounds is that wherein R3 is ethyl.
Within these preferred, more preferred groups, and particularly preferred
groups, a
more particularly preferred group of compounds is that wherein R4 is
benzoxazol-2-yl.
3. Yet another preferred group of compounds of Formula I is represented by
Formula Id:
R2 H O
R~ H~N~R4
O R
Id
wherein:
Rl is a group of formula:
)
Y X
, za-~b ~_ r
'.
(ii)
Xa
Z~
~a-~b
Xb
(V)
X
Q
i
~ (xi)
Attorney Docket No. 1051-PCT 25
CA 02484011 2004-10-26
WO 03/097617 PCT/US03/15486
Y
H02C\ Z°~
\ / Za-Zb
X ;
(X111)
Y
H02C~ Za-
\ / \ / ~_
x
(xiv)
COOH
HO~C~ Za-
\ / \ / ~_
. r
' X ; or
(xv)
Ra
Q'~ a ~ .
where:
Za is -CX- or N- and Zb and Z° are independently selected from -CH-
and N-
. provided that if an Rl group contains Za, Zb, and Z~ simultaneously then,
when Z° is N-,
then Za is N- or -CX- and Zb is -CH-; and when Zb is N- then both Za and
Z° cannot be -
N- simultaneously and further provided that X is not hydrogen; and
Q, Q', X, Y, Xa, X~, RZ, R3, R4 and R8 are as defined in the Summary of the
Invention for Formula I.
15~ ~ More preferably, X and Y are independently selected from hydrogen,
chloro,
methyl, methoxy, trifluoromethyl, or trifluoromethoxy, preferably hydrogen,
chloro, methyl,
or methoxy;
Xa, and Xb are independently selected from methyl, chloro, fluoro, methoxy,
. ~ trifluoromethyl, or trifluoromethoxy, preferably chloro, methyl, or
methoxy; and
~ RZ is selected from the group consisting of cyclohexyl, cycloheptyl, thiazol-
2-
ylmethyl, 2-ethylbutyl, pyrazol-1-ylmethyl, 2-methylpropyl, 2,4,4-
trimethylpentyl, 2-napth-
1-ylpropyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-phenylpropyl, 2-(2-
. . methoxyphenyl)propyl, 4-methylindol-3-ylmethyl, 2-(2,5-
dimethylphenyl)propyl,
benzyloxymethyl, 2-(2,4-dimethylphenyl)propyl, 2-(2,4-dichlorophenyl)-propyl,
2,6-
2$ ~ difluorobenzyl, 2,5-difluorobenzyl, and 2,3-difluorobenzyl; preferably
2,6-difluorobenzyl or
. . ~ Attorney Docket No. 1051-PCT 26
CA 02484011 2004-10-26
WO 03/097617 PCT/US03/15486
2-phenylpropyl and the stereochemistry to which RZ is attached is (S~ when the
Prelog rule
places the order of the substituent 1) N, 2) -COOH, 3) RZ and 4) H; and (R)
when the Prelog
rule places the order of the substituent 1) N, 2) RZ, 3) -COOH and 4) H; and
the stereochemistry at the carbon atom to which R3 is attached is (S~.
S Within the above preferred and more preferred groups, an even more preferred
group
- of compounds is that wherein Rl is 3-chloro-2-(2,6-dichlorophenyl)pyridin-5-
yl or 3-(2
chlorophenyl)isoxazol-5-yl; R3 is ethyl, and R4 is benzoxazol-2-yl.
4. Yet another preferred group of compounds of Formula I is that wherein
Rl° is
hydrogen, hydroxy, alkoxy; and Rl l is hydroxy or alkoxy; or Rl° and Rl
l together with the
10, carbon atom to which they are attached form -O-(CZ-C4)alkylene-O- wherein
the alkylene
chain is optionally substituted with one or two alkyl.
Within this group a more preferred group of compounds is that wherein Rl, RZ,
R3
and R4 are preferred groups disclosed in groups 1-3 above.
5. Yet another preferred group of compounds of Formula I is that wherein:
15 ~ Rl is 2'-Cl-biphenyl-4-yl, 2,3-diphenylthiophen-5-yl, 2-(2-
Clphenyl)pyridin-5-yl,
2',3-diCl-biphen-4-yl, 5'-carboxy-2'chlorobiphen-4-yl, 3-vinylphenyl, 4-
phenoxyphenyl, 4-
aoetylamino-3-methyl-phenyl, 3,5-di(2-methoxyphenyl)-phenyl, 4-morpholin-4-
ylphenyl, 1-
methyl-3-trifluoromethyl-1H-thieno[2,3-c]pyrazol-5-yl, or 4-tert-butylphenyl;
RZ is 2,6-difluorobenzyl, 2(S')-phenylpropyl, cyclohexyl, thiazol-2-ylmethyl,
20 ~ cycloheptyl, 2-ethylbutyl, pyrazol-1-yl-methyl, 2,4,6-trifluorobenzyl,
indol-3-ylmethyl, N-
phenyl-N methylaminomethyl, methyl, 4-methylindol-3-ylmethyl, or hydrogen;
RZa is hydrogen or RZ and R2a together with the carbon atom to which they are
attached form cycloheptyl,
R3 is ethyl, yz-propyl, ra-butyl;
25 ~~ R4 is benzoxazol-2-yl, oxazolo[4,5-b]pyridin-2-yl, 2-pyridin-3-yl-
[1,3,4]-oxadiazol-
. ~ . 5-yl, 2-pyridin-4-yl-[1,3,4]-oxadiazol-5-yl, 2-phenyl-[1,3,4]-oxadiazol-
5-yl, 2-ethyl-[1,3,4]-
. ~ oxadiazol-5-yl, 2-phenyl-[1,3,4]-oxadiazol-5-yl, or 2-tert-butyl-[1,3,4]-
oxadiazol-5-yl; and
Rl° and Rl l together with the carbon atom to which they are attached
form -C=O.
6. Yet another preferred group of compounds of Formula I is that wherein:
30 ~ Rl is 2'-chlorobiphen-4-yl, 2',3-dichlorobiphenyl-4-yl, 2',6'-
dichlorobiphen-4-yl,
. 2',6'-dimethylbiphen-4-yl, 2'-methylbiphen-4-yl, 2'-fluorobiphen-4-yl; 4-
.~ trifluoromethoxyphenyl, 4-(2-butyl)phenyl, 3,5-diphenylphenyl, 2,3-
diphenylthiophen-5-yl,
'. 2-(2-methylphenyl)furan-5-yl, 2-(2-methoxyphenyl)furan-5-yl, 3-methoxy-2-(2-
methylphenyl)thiophen-4-yl, 3-methoxy-2-(2-methoxyphenyl)thiophen-4-yl, 2,3-
di(2-
Attorney Docket No. 1051-PCT 27
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WO 03/097617 PCT/US03/15486
rilethoxyphenyl)thiophen-5-yl, 3,5-di(2-methoxyphenyl)phenyl, 3,5-di(3-
methoxyphenyl)phenyl, 3,5-di(thiophen-3-yl)phenyl, 3,5-di(pyridin-4-yl)phenyl,
2,3-di(2-
methylphenyl)thiophen-5-yl, 4-tent-butylphenyl, 2,3-di(furan-2-yl)thiophen-5-
yl, 3,5-
di(furan-2-yl)phenyl, 4-(2-methylphenyl)thiophen-2-yl, 4-(2-
methoxyphenyl)thiophen-2-yl,
2'-chlorobiphen-3-yl, 2'-methyl-4-chlorobiphenyl-3-yl, 3,5-di(2-
chlorophenyl)phenyl, 2,3-
di(2-chlorophenyl)thiophen-5-yl, 1-(4-aminosulfonylphenyl)-5-(4-
chlorophenyl)pyrazol-3-
yl, 2-(2,6-dichlorophenyl)furan-5-yl, 2,3-diphenylthiophen-5-yl, 4,5-
diphenylthiazol-2-yl,
3-trifluoromethyl-1-methylthieno[2,3-c]pyrazol-5-yl, 3-methylbiphen-4-yl, 2'-
methoxybiphen-4-yl, 2'-trifluoromethylbiphen-4-yl, 2,'-methyl-3-chlorobiphen-4-
yl, 2-(2-
chlorophenyl)pyridin-5-yl, 2-(2,6-dichlorophenyl)pyridin-5-yl, 2-(2-
trifluoromethyl-
phenyl)pyridin-5-yl, 4-(3-methylpyridin-2-yl)phenyl, 2-(2-chlorophenyl)-3-
chloropyridin-5-
yl, 4'-carboxy-2'-chlofobiphen-4-yl, 4'-carboxy-2'-fluorobiphen-4-yl, 4'-
carboxy-2'-
methylbiphen-4-yl, 5'-carboxy-2'-methylbiphen-4-yl, 4-(3-methylpyridin-2-
yl)phenyl, 5'-
. ~ carboxy-2'-chlorobiphen-4-yl, 2-(4-carboxy-2-chlorophenyl)pyridin-5-yl, 2-
(5-carboxy-2-
15. ~ chlorophenyl)-pyridin-5-yl, 4-(5-carboxy-2-methylthiophen-3-yl)phenyl, 3-
chloro-2-(2,6-
dichlorophenyl)-pyridin-5-yl, 3-(2-chlorophenyl)isoxazol-5-yl or 4-(3-methoxy-
phenyl)thiophen-2-yl. More preferably, Rl is 2'-chlorobiphen-4-yl, 2',3-
dichlorobiphenyl-
4-yl, 2',6'-dichlorobiphen-4-yl, 2',6'-dimethylbiphen-4-yl, 2'-methylbiphen-4-
yl, 2'-
fluorobiphen-4-yl; 4-trifluoromethoxy-phenyl, 4-(2-butyl)phenyl, 3,5-
diphenylphenyl, 2,3-
~ diphenylthiophen-5-yl, 2-(2-methylphenyl)-furan-5-yl, 2-(2-
methoxyphenyl)furan-5-yl, 3-
methoxy-2-(2-methylphenyl)thiophen-4-yl, 3-methoxy-2-(2-methoxyphenyl)thiophen-
4-yl,
2;3-di(2-methoxyphenyl)thiophen-5-yl, 3,5-di(2-methoxyphenyl)phenyl, 3,5-di(3-
methoxyphenyl)phenyl, 3,5-di(thiophen-3-yl)phenyl, 3,5-di(pyridin-4-yl)phenyl,
2,3-di(2-
methylphenyl)thiophen-5-yl, 4-test-butylphenyl, 2,3-di(furan-2-yl)thiophen-5-
yl, 3,5-
di(furan-2-yl)phenyl, 4-(2-methylphenyl)thiophen-2-yl, 4-(2-methoxyphenyl)-
thiophen-2
yl, 2'-chlorobiphen-3-yl, 2'-methyl-4-chlorobiphenyl-3-yl, 3,5-di(2-
chlorophenyl)-phenyl,
-~ 2,3-di(2-chlorophenyl)thiophen-5-yl, 1-(4-aminosulfonylphenyl)-5-(4-
chlorophenyl)
pyrazol-3-yl, 2-(2,6-dichlorophenyl)furan-5-yl, 2,3-diphenylthiophen-5-yl, 4,5-
diphenylthiazol-2-yl, 3-trifluoromethyl-1-methylthieno[2,3-c]pyrazol-5-yl, 2-
(2-
chlorophenyl)pyridin-5-yl, 2-(2',6'-dichlorophenyl)pyridin-5-yl, 2-(2-
trifluoromethylphenyl)-pyridin-5-yl, 4-(3-methylpyridin-2-yl)phenyl, 2-(2-
chlorophenyl)-3-
chloropyridin-5-yl, 4'-carboxy-2'-chlorobiphen-4-yl, 4'-carboxy-2'-
fluorobiphen-4-yl, 4'-
oarboxy-2'-methylbiphen-4-yl, 5'-carboxy-2'-chlorobiphen-4-yl, 2-(4-carboxy-2-
chlorophenyl)pyridin-5-yl, 2-(5-carboxy-2-chlorophenyl)pyridin-5-yl, 4-(5-
carboxy-2-
Attorney Docket No. 1051-PCT 28
CA 02484011 2004-10-26
WO 03/097617 PCT/US03/15486
methylthiophen-3-yl)phenyl, or 4-(3-methoxy-phenyl)thiophen-2-yl. Even more
preferably,
Rl is 2'-chlorobiphen-4-yl, 2',6'-dichlorobiphen-4-yl, 2-(2-
chlorophenyl)pyridin-5-yl, or
2',3-dichlorobiphen-4-yl.
' 7, Yet another preferred group of compounds of Formula I is that wherein R2
is
5~ selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl,
2-ethylbutyl,
thiazol-2-ylmethyl, pyrazol-1-ylmethyl, 1,2,3-triazol-1-ylmethyl, 1,2,4-
triazol-1-ylmethyl,
. pyrrol-1-ylmethyl, imidazol-1-ylmethyl, tetrazol-1-ylmethyl, 2-methylpropyl,
2,4,4-
trimethylpentyl, 4-methylindol-3-ylmethyl, 2-napth-1-ylpropyl,
benzyloxymethyl, 1-
phenylcyclopropylmethyl, 1-phenylcyclobutylrnethyl, 2-phenylprop-2-enyl, 2-
phenyl-2-
xnethylpropyl, 2-phenylpropyl, 2-phenylbutyl, benzyl (where the phenyl ring in
the benzyl
. . group is substituted at he 2 and 6 positions with groups independently
selected from
methyl, chloro, fluoro, trifluoromethyl, methoxy, trifluoromethoxy, or
difluoromethoxy and
at the 4 position with hydrogen, methyl, ethyl, propyl, chloro, fluoro,
trifluoromethyl,
methoxy, 2-methoxyethyloxy, 2-dimethylaminoethyloxy, trifluoromethoxy,
difluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, cyano, amino,
methylamino
' or dimethylamino). Rz is preferably selected from the group consisting of
cyclohexyl,
cycloheptyl, thiazol-2-ylmethyl, 2-ethylbutyl, pyrazol-1-ylmethyl, 2,4,4-
trimethylpentyl, 2-
napth-1-ylpropyl, 2-phenylprop-2-enyl, 2-phenyl-2-methylpropyl, 2-
phenylpropyl, 2-(2-
. ~ methoxyphenyl)propyl, 4-methylindol-3-ylmethyl, 2-(2,5-
dimethylphenyl)propyl,
20_ ~ benzyloxymethyl, 2-(2,4-dimethylphenyl)-propyl, 2-(2,4-dichlorophenyl)-
propyl, 2,6-
difluorobenzyl, 2,5-difluorobenzyl, and 2,3-difluorobenzyl.
A number of different preferences have been given above, and following any one
a of these preferences results in a compound of this invention that is more
presently
. ~ , preferred than a compound in which that particular preference is not
followed. However,
~ these preferences are generally independent and additive; and following more
than one
of these preferences may result in a more presently preferred compound than
one in
which fewer of the preferences are followed. Additional aspects of this
invention are
. disclosed in Applicants' U.S. Provisional Applications Serial Nos.
60/380,311, filed on
May 14, 2002, and 60/422,337, filed on October 30, 2002, the disclosures of
which are
~ ' incorporated herein by reference in their entirety.
Attorney Docket No. 1051-PCT 29
CA 02484011 2004-10-26
WO 03/097617 PCT/US03/15486
0 0
N N
.
.,
r.. .'., T
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Attorney Docket No. 1051-PCT 30
CA 02484011 2004-10-26
WO 03/097617 PCT/US03/15486
?, ~, >,
o ~ ~ U' ~ v~
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0
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~,
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Attorney Docket No. 1051-PCT 31
CA 02484011 2004-10-26
WO 03/097617 PCT/US03/15486
>,
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Attorney Docket No. 1051-PCT 32
CA 02484011 2004-10-26
WO 03/097617 PCT/US03/15486
>, >, ~ ~,
N
b
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' Attorney Docket No. 1051-PCT 33
CA 02484011 2004-10-26
WO 03/097617 PCT/US03/15486
>, >,
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Attorney Docket No. 1051-PCT 34
CA 02484011 2004-10-26
WO 03/097617 PCT/US03/15486
GENERAL SYNTHETIC SCHEME
Compounds of this invention can be made by the methods depicted in the
reaction
schemes shown below.
The starting materials and reagents used in preparing these compounds are
either
available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee,
Wis.) or
- Bachem (Torrance, Calif.) or are prepared by methods known to those skilled
in the art
following procedures set forth in references such as Fieser and Fieser's
Reagents for
Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry
of
_ Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science
Publishers, 1989);
' Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's
Advanced Organic
Chemistry, (John Wiley and Sons, 4th Edition) and Larock's Comprehensive
Organic
Transformations (VCH Publishers Inc., 1989). These schemes are merely
illustrative of
some methods by which the compounds of this invention can be synthesized, and
various
~ ~ modifications to these schemes can be made and will be suggested to one
skilled in the art
having referred to this disclosure.
The starting materials and the intermediates of the reaction may be isolated
and
. purified, if desired, using conventional techniques, including but not
limited to filtration,
distillation, crystallization, chromatography and the like. Such materials may
be
~ characterized using conventional means, including physical constants and
spectral data.
Unless specified to the contrary, the reactions described herein take place at
atmospheric pressure over a temperature range from about-78 °C to about
150 °C, more
preferably from about 0 °C to about 125 °C and most preferably
at about room (or ambient)
temperature, e.g.,
~ about 20 °C.
Compounds of Formula I where Rl, R2, RZa, R3, R4 are as defined in the Summary
of
the Invention and Rl° is hydrogen and Rl l is hydroxy or Rl° and
Rl l together with the
carbon atom to which they are attached form carbonyl can be prepared as shown
in Scheme
1 below.
Attorney Docket No. 1051-PCT 35
CA 02484011 2004-10-26
WO 03/097617 PCT/US03/15486
Scheme 1
OH O O R3
R4 NH2 +, R\ 'NH OH _ R\'NH N R4
R3 jIOI( Rz RZa ~ ~O R2 R2a H OH
1 2 3
O R3
-~ R ~ N H R4
N
O R2 R2a H O
I
Reaction of an~alpha-aminoalcohol compound of formula 1 with an N acylated
amino acid of formula 2 provides a compound of formula 3. The reaction is
typically
~ carried out in the presence of a suitable coupling agent
e.g., benzotriazole-1-yloxytrispyrrolidinophosphonium hexafluorophosphate
(PyBOP~),
O-benzotriazol-1-yl-N,N,N',N'-tetramethyl-uronium hexafluorophosphate (HBTU),
O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyl-uronium hexafluorophosphate
(HATlJ),
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), or
10' 1,3-dicyclohexylcarbodiimide (DCC), optionally in the presence of 1-
hydroxybenzotriazole
(HOBT), and a base such as N,N diisopropylethylamine, triethylamine, N
methylmorpholine, and the like. The reaction is typically carried out at 20 to
30 °C,
preferably at about 25 °C, and requires 2 to 24 h to complete. Suitable
reaction solvents are
inert organic solvents such as halogenated organic solvents (e.g., methylene
chloride,
, chloroform, and the like), acetonitrile, N,1V dimethylformamide, ethereal
solvents such as
tetrahydrofuran, dioxane, and the like. Preferably, the reaction is carned out
with HOBt,
and EDC in dichloromethane.
Alternatively, this reaction can be carried out by first converting 2 into an
active acid
derivative such as an acid chloride or succinimide ester and then reacting it
with an amine
' of formula 1. The reaction typically requires 2 to 3 h to complete. The
conditions utilized
. in this reaction depend on the nature of the active acid derivative. For
example, if it is an
acid chloride derivative of 2, the reaction is carried out in the presence of
a suitable base
. . (e.g. triethylamine, diisopropylethylamine, pyridine, and the like).
Suitable reaction
. . ~ solvents are polar organic solvents such as acetonitrile, N,N
dimethylformamide,
. dichloromethane, or any suitable mixtures thereof.
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Compounds of formula 1 can be prepared under deprotonation reaction conditions
by treating benzoxazole, oxazolo[4,5-b]pyridine, 2-pyridin-3-yloxadiazole, 2-
pyridin-4-yl-
oxadiazole, 2-phenyloxadiazole, and the like, with a Grignard reagent such as
isopropylmagnesium chloride and then reacting the resulting organomagnesium
reagent
vwith an alpha-(N protected amino)aldehyde of formula R3CH(NHPG)CHO, where R3
is as
defined in the Summary of the Invention and PG is a suitable amino protecting
group (such
as test-butyoxycarbonyl, benzyloxycarbonyl, or benzyl) to provide an N
protected
compound of formula 1 after treatment with an aqueous acid or buffer. Removal
of the
amino protecting group then provides a compound of formula 1.
The addition reaction is typically carned out in an ethereal organic solvent
such as
. tetrahydrofuran, diethyl ether, dioxane, and the like, preferably
tetrahydrofuran, at a
- temperature from about -78 °C to about 40 °C. Preferably, the
reaction is carned out from
about-10 °C to about 40 °C, more preferably from about -10
°C to about 10 °C. The
reaction typically requires an hour to complete. 'The nucleophilic addition
reaction is
15' _ typically carned out from about -10 °C to about room temperature.
Compounds of formula
R3CH(NHPG)CHO are prepared from commercially available starting materials by
methods
well known in the art.
The reaction conditions employed for removal of the amino protecting group
depends on the nature of the protecting group. For example, if the protecting
group is te~t-
- butoxycarbonyl, it is removed under acid reaction conditions. Suitable acids
are
trifluoroacetic acid (TFA), hydrochloric acid, and the like. If the protecting
group is benzyl
or benzyloxycarbonyl, it is removed under catalytic hydrogenation reaction
conditions.
Suitable catalyst are palladium, platinum, rodium based catalysts and others
known in the
. art. Other suitable reaction conditions for their removal can be found in
Greene, T.W.; and
. Wuts, P. G. M.; Protecting Groups ih Organic Syntlaesis; John Wiley & Sons,
Inc. 1999.
The reaction is carried out in an inert organic solvent methylene chloride,
tetrahydrofuran,
dioxane, dimethylformamide, and the like.
Compounds of formula 2 can be prepared by methods well known in the art. Some
- such procedures are described in PCT Application Publication No. WO 00/55144
the
.. ~ disclosure of which is incorporated herein in its entirety. For example,
a compound of
formula 2 can be prepared by reacting an amino acid of formula R2CH(NHZ)COOH
with an
. . acid derivative of the formula R1COL where L is a suitable leaving group
such as chloro
and the like. Specifically, a compound of formula 2 where R2 is 2,6-
difluorobenzyl and Rl
- ~ ~is 2'-chlorobiphenyl-4-yl can be prepared by reacting 2,6-
difluorophenylalanine with 2'-
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chlorobiphenyl-4-ylcarbonyl chloride in the presence of base such as
triethylamine and in a
suitable organic solvent such as acetonitrile. Amino acids of the formula
RZCH(NHZ)COOH are either commercially available or they can be prepared by
methods
known in the art. For example, 2-amino-3-(4-methylindol-3-yl)propionic acid
can be
5- bought from Bachem. Syntheses of some amino acids are described in working
examples
below.
Acid derivatives of the formula R1COL where L is a halogen can be prepared by
reacting the corresponding acids with a halogenating agent such as oxalyl
chloride, thionyl
chloride, and the like. Acids of formula R1COOH are either commercially
available or they
can be prepared from commercially available starting materials by methods
known in the
art. For example, 1-(4-aminosulfonylphenyl)-5-(4-chlorophenyl)pyrazol-3-
ylcarboxylic
acid and 1-methyl-3-trifluoro-1H-thieno[2,3-c]pyrazol-4-ylcarboxylic acid are
commercially available from Bionet.
Oxidation of hydroxy group in 3 is tamed out with a suitable oxidizing agent
such
. as Dess-Martin Periodinane in a halogenated organic solvent such as
methylene chloride,
chloroform, carbon tetrachloride, and the like, or a mixture of TEMPO/bleach
then provides
a compound of Formula I.
A compound of Formula I can be converted to other compounds of Formula I. For
example, a compound of Formula I where Rl° is alkoxy can be prepared
from a
, corresponding compound of Formula I where Rl° is hydroxy under
alkylating reaction
~' conditions. A compound of Formula I where Rl° and Rl l together with
the carbon atom to
which they are attached form C=O can be reacted with a diol such a ethylene
glycol to form
a compound where Rl° and R11 together form -O-(CZ)alkylene-O-.
- Pharmacology and Utility
The compounds of the invention are cysteine protease inhibitors. In particular
the
compounds of the invention inhibit the activity of cathepsins B, L, K, F
and/or S and, as
such, are useful for treating diseases in which cathepsin B, L, K, F and/or S
activity
contributes to the pathology and/or symptomatology of the disease. For
example, the
. . compounds of the invention are useful in treating tumor invasion and
metastasis, in
particular as anti-angiogenic agents, rheumatoid arthritis, osteoarthritis,
pneumocystis
carinii, acute pancreatitis, inflammatory airway disease, atherosclerosis,
restenosis, and
bone and joint disorders. Furthermore, the compounds of the invention are
useful in
treating bone resorption disorders, e.g., osteoporosis. The compounds of the
invention also
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are useful in treating autoimmune disorders, including, but not limited to
juvenile- onset
diabetes, multiple sclerosis, pemphigus vulgaris, Graves disease, myasthenia
gravis,
systemic lupus erythematosus, rheumatoid arthritis and Hashimoto's
thyroiditis. The
compounds of the invention also are useful in treating allergic disorders,
including, but not
limited to asthma; and allogeneic immune reponses, including, but not limited
to, organ
transplants or tissue grafts.
The cysteine protease inhibitory activities of the compounds of the invention
can be
determined by methods known to those of ordinary skill in the art. Suitable
ira vitro assays
for measuring protease activity and the inhibition thereof by test compounds
are known.
10. Typically, the assay measures protease-induced hydrolysis of a peptide-
based substrate.
Details of assays for measuring protease inhibitory activity are set forth in
Biological
Examples 1-5, infra.
Administration and Pharmaceutical Compositions
, In general, compounds of Formula I will be administered in therapeutically
effective
amounts via any of the usual and acceptable modes known in the art, either
singly or in
combination with another therapeutic agent. A therapeutically effective amount
may vary
widely depending on the severity of the disease, the age and relative health
of the subject,
the potency of the compound used and other factors. For example,
therapeutically effective
~ amounts of a compound of Formula I may range from about 10 micrograms per
kilogram
body weight (~,g/kg) per day to about 20 milligram per kilogram body weight
(mg/kg) per
day, typically from about 100 ~,g/leg/day to about 10 mg/kg/day. Therefore, a
therapeutically effective amount for a 80 kg human patient may range from
about 1 mg/day
to about 1.6 g/day, typically from about 1 ~g/day to about 100 mg/day. In
general, one of
. ordinary skill in the art, acting in reliance upon personal knowledge and
the disclosure of
' this Application, will be able to ascertain a therapeutically effective
amount of a compound
of Formula I for treating a given disease.
The compounds of Formula I can be administered as pharmaceutical compositions
by one of the following routes: oral, systemic (e.g., transdermal, intranasal
or by
30' suppository) or parenteral (e.g., intramuscular, intravenous or
subcutaneous). Compositions
can take the form of tablets, pills, capsules, semisolids, powders, sustained
release
formulations, solutions, suspensions, elixirs, aerosols, or any other
appropriate composition
. _ and are comprised of, in general, a compound of Formula I in combination
with at least one
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pharmaceutically acceptable excipient. Acceptable excipients are non-toxic,
aid
administration, and do not adversely affect the therapeutic benefit of the
active ingredient.
Such excipient may be any solid, liquid, semisolid or, in the case of an
aerosol composition,
gaseous excipient that is generally available to one of skill in the art.
. Solid pharmaceutical excipients include starch, cellulose, talc, glucose,
lactose,
sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate,
sodium stearate,
glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid
and semisolid
excipients may be selected from water, ethanol, glycerol, propylene glycol and
various oils,
- including those of petroleum, animal, vegetable or synthetic origin (e.g.,
peanut oil, soybean
10~ oil, mineral oil, sesame oil, or the like). Preferred liquid carriers,
particularly for injectable
solutions, include water, saline, aqueous dextrose and glycols.
The amount of a compound of Formula I in the composition may vary widely
depending upon the type of formulation, size of a unit dosage, kind of
excipients and other
. ~ factors known to those of skill in the art of pharmaceutical sciences. In
general, a
composition of a compound of Formula I for treating a given disease will
comprise from
O.O l wt% to 10 wt%, preferably 0.3 wt% to 1 wt%, of active ingredient with
the remainder
being the excipient or excipients. Preferably the pharmaceutical compositions
are
administered in a single unit dosage form for continuous treatment or in a
single unit dosage
form ad libitum when relief of symptoms is specifically required.
Representative
pharmaceutical formulations containing a compound of Formula I are described
below.
EXAMPLES
The following preparations and examples are given to enable those skilled in
the
art to more clearly understand and to practice the present invention. They
should not be
, considered as limiting the scope of the invention, but merely as being
illustrative and
representative thereof.
Synthetic Examples
General Procedures
3p ~ Example A
Synthesis of 2(S~-amino-1-(3-phenyl-[1,2,4Joxadiazol-5-yl)-butan-1-of
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H2N
H3C
3-tart-Butoxycarbonylamino-2-hydroxy-pentanoic acid (500 mg, 2.14 mmol) was
combined with EDC (600 mg, 3.14 mmol), HOBt (600 mg, 3.92 mmol), and N hydroxy-
~ benzamidine (292 mg, 2.14 mmol). Dichloromethane (10 mL) was added and then
4-
methylmorpholine (1 mL). The mixture was stirred at ambient temperature for 16
h. After
dilution with ethyl acetate (200 mL), the solution was washed with water (30
mL), saturated
aqueous NaHC03 solution and brine, dried with MgS04, filtered, and evaporated
under
vacuum. The crude product was dissolved in pyridine (10 mL) and heated at 80
°C for 15 h.
. The pyridine was evaporated under vacuum and the residue was purified by
flash
chromatography on silica gel (eluent: ethyl acetate) to yield (290 mg
0.83mmo1). The
oxadiazole (145 mg, 0.41 mmol) was dissolved in CHZCl2 (4 mL) and TFA (4 mL)
was
added. After stirring for 1 h, the mixture was evaporated to dryness to yield
2(,S')-amino-1-
(3-phenyl-[1,2,4]oxadiazol-5-yl)-butan-1-of as a TFA salt.
15'
Example B
Synthesis of 2(RSV-benzyloxycarbonylamino-4(RS7-(2-methoxyphenyl)pentanoic
acid
o~
0
~ OH
O_ _N
H O
To d,l-2-methoxy-a,-methylbenzyl alcohol (0.5 g, 3.29 mmol) was added 48% aq.
HBr (2 mL) and the reaction mixture was stirred rapidly for 1.5 h. The
reaction mixture
was diluted with hexane (30 mL), washed with water, dried with MgS04,
filtered, and
evaporated under vacuum. The crude d,l-2-methoxy-a-methylbenzyl bromide was
added to
25_ ~ a solution of tributyltin hydride (0.67 mL, 2.49 mmol), Z-dehydroalanine
methyl ester (0.25
g, 1.06 mmol), and 2,2'-azobisisobutyronitrile (15 mg, 0.09 mmol) in benzene
(5 mL). The
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reaction mixture was heated at 80 °C under a nitrogen atmosphere for 5
h. Benzene was
removed under vacuum and the residue was dissolved in methanol (20 mL). 2N KOH
(5
' mL) was added and the mixture was rapidly stirred at room temperature over
night.
Methanol was removed under vacuum and the residue was diluted with water (20
mL). The
~ aqueous solution was washed with ether to remove the tin by products. The
aqueous layer
was acidified with 6 N HCl (aq.) and the product was extracted with ethyl
acetate. The
combined organic layers were washed with brine, dried with MgS04, filtered,
and
evaporated under vacuum to give 2-benzyloxy-carbonylamino-4-(2-
yiethoxyphenyl)pentanoic acid (190 rng, 0.53 mmol) as a mixture of
diastereomers in
_ sufficiently pure form to be used without further purification. MS: (M++H)
358, (M+-IT)
356.
Following the procedure described above, and utilizing appropriate starting
materials the following amino acids were prepared:
2-benzyloxy-carbonylamino-4-(2-methoxyphenyl)hexanoic acid;
15~ ~. 2-benzyloxy-carbonylamino-4-(4-fluorophenyl)pentanoic acid;
- . 2-benzyloxy-carbonylamino-4-(4-chlorophenyl)pentanoic acid;
2-benzyloxy-carbonylamino-4-(4-methoxyphenyl)pentanoic acid;
2-benzyloxy-carbonylamino-4-(2-trifluoromethylphenyl)pentanoic acid;
2-benzyloxy-carbonylamino-4-(3-trifluoromethylphenyl)pentanoic acid;
. 2-benzyloxy-carbonylamino-4-(napth-1-yl)pentanoic acid;
2-benzyloxy-carbonylamino-4-(2,6-dimethylphenyl)pentanoic acid;
. ' 2-benzyloxy-carbonylamino-4-(2,4-difluorophenyl)pentanoic acid;
2-benzyloxy-carbonylamino-4-(2,4-dimethylphenyl)pentanoic acid;
2-benzyloxy-carbonylamino-4-(2,5-dimethylphenyl)pentanoic acid; and
25' . 2-benzyloxy-carbonylamino-4-(2,4-dichlorophenyl)pentanoic acid.
. ' The benzyloxycarbonyl group can be removed as described in Example C below
to
give the corresponding free amino acid.
Example C
Synthesis of 2(S~-2,6-difluorophenylalanine
F
F
H2N COOH
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Step 1
N (Benzyloxycarbonyl)-a-phosphonoglycine trimethyl ester (Aldrich No. 37,635-
3;
6.7 g, 20 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (Aldrich No.l3, 900-9;
3.3 mL, 22
mmol) were dissolved.in methylene chloride (11 mL) and stirred at room
temperature for 15
. min., and then cooled to < -30 °C. A solution of 2,6-
difluorobenzaldehyde (1.9 mL, 20
mmol) in methylene chloride (25 mL) was added to the reaction mixture dropwise
over 20
min. The reaction mixture was stirred for another 20 min., and then allowed to
warm up to
room temperature for 30 min. The reaction mixture was then poured into ethyl
ether (300
mL) and washed with 1 N HCI, brine and dried over MgS04. Rotary evaporation
gave 2-
, benzyloxycarbonylamino-3-(2,6-difluorophenyl)acrylic acid methyl ester. This
crude
product was purified by chromatography on a Medium Pressure Liquid Column
(MPLC)
eluting with 20% ethyl acetate/ 80% hexane to give pure product (5 g, 72%
yield, liquid).
Step 2
A mixture of 2-benzyloxycarbonylamino-3-(2,6-difluorophenyl)acrylic acid
methyl
. ester (14.4 mmol), and catalyst, (+)-1,2-bis-[(2S, SS)2, 5-
diethylphopholano]benzene
(cyclooctadiene)rhodium (1) trifluoromethanesulfonate (Strem. Chemical No. 45-
0151; 104
mg, 0.14mmo1) was dissolved in ethanol (150 mL). Hydrogenation was performed
at 50 psi
H~ at room temperature over 2 days. The solvent was then removed by rotary
evaporation
to give 2(S)-benzyloxycarbonylamino-3-(2,6-difluorophenyl)propionic acid
methyl ester.
20- Step 3
2(S)-Benzyloxycarbonylamino-3-(2,6-difluorophenyl)propionic acid methyl ester
(5
g, 14.4 mmol) was dissolved in methanol (60 mL) and cooled on ice. 1 N NaOH
(22 mL,
22 mmol) was added dropwise over 15 min. The reaction mixture was removed from
cooling and continue stirnng at room temperature for 4 h. The solvent was then
removed by
rotary evaporation. The residue was treated with water (100 mL) and then with
1 N HCl to
adjust the pH to 4. The product was extracted with ethyl acetate (300 mL, 200
mL).
Evaporation of the solvent and crystallization of the residue from methylene
chloride/hexane gave 2(S)-benzyloxycarbonylamino-3-(2,6-
difluorophenyl)propionic acid
(4.6 g, 13.7 mmol, 94% yield).
30' ~. St- ep 4
2(S)-Benzyloxycarbonylamino-3-(2,6-difluorophenyl)-propionic acid was
hydrogenated at 50 psi in ethanol (25 mL) in the presence of 5% palladium on
activated
carbon (600 mg) for 24 h. The catalyst was removed by filtration through
celite and the
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solvent evaporated to give a residue which was crystalized from ethyl ether to
give 2(,S~-2,6-
difluorophenylalanine (2.2 g, 11 mmol, 80% yield). 1H NMR (DMSO-d6): 8 7.28
(m, 1H),
7.0 (t, J 7.6 Hz, 2H), 2.77 (m, 2H). MS: 202.2 (M+1), 199.7(M-1).
Example D
Synthesis of 2(RSV-amino-4(RS~-6,6-trimethylheptanoic acid
HZN ~COOH
Step 1
To a mixture of the 3,5,5-trimethylhexanal (17.4 mL, 0.10 mol), ammonium
chloride
(53.5 g, 0.205 mol) and diethyl ether (113 mL) was added sodium cyanide (7.35
g, 0.15
mol) in water (38 mL). The reaction mixture was allowed to stir vigorously for
16 h. The
layers were separated. . The aqueous layer was extracted with diethyl ether.
The combined
organic layer was then extracted with 1 N HCI. Saturated sodium bicarbonate
was then
~ added until 1-cyano-3,5,5-trimethyl-hexylarnine was completely precipitated.
Vacuum
y filtration and washing with 5 mL ice cold water followed by lyophilization
gave 1-cyano-
' 3,5,5-trimethylhexylamine (5.805 g, 0.034 mol, 34.5%) as a white solid.
Step 2
1-Cyano-3,5,5-trimethylhexylamine (1.02 g, 5.0 mmol) was treated with 6 N HCl
2Q . ~ (10 mL) and heated at reflux for 30 h. The reaction mixture was allowed
to cool to room
temperature. Water (50 mL) was added, and the mixture was washed with diethyl
ether.
The aqueous layer was basified to pH 8.5 with 2 M KOH. A white precipitate
formed
' which was collected by vacuum filtration and lyophilized to give 2(RS~-amino-
4(R~,6,6-
trimethyl-heptanoic acid (364 mg).
Example E
Synthesis of 2(R~-amino-4-methyl-4-phenylpentanoic acid
HEN COOH
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Step 1
4-Methyl-4-phenyl-1-pentene was prepared by reacting 2-phenyl-2-propanol with
3-
(trimethylsilyl)propene by the method of Cella, J. Org. Chern., 1982, 47, 2125-
2130.
Step 2
~ 4-Methyl-4-phenyl-1-pentene was ozonolyzed at-78 °C in
dichloromethane
followed by dimethyl sulfide quenching to give crude product which was
purified by silica
gel chromatography to give 3-methyl-3-phenylbutanal which was then converted
to the title
compound by proceeding as described in Example D above.
Example F
Synthesis of 2(~-amino-4-phenylpent-4-enoic acid
H2N COOH
Step 1
Methyl triphenylphosphonium bromide (1.12 g, 3.14 mmol, 2.0 equiv.) was
. dissolved in THF (15 mL) and cooled to 0 °C. Sodium
bis(trimethylsilyl)amide (3.14 mL)
was added and the reaction mixture was stirred for 30 min. 2(,S~-
Benzyloxycarbonyl-amino-
3-benzoylpropionic acid ethyl ester (0.54 g, 1.57 mmol, 1.0 equiv. prepared by
procedures
outlined in Lin, W., et. al., Syhtlaesis 2001, No. 7, 1007-1009 was dissolved
in THF (5 mL)
and added to the reaction. After warming to room temperature, the reaction
mixture was
quenched with saturated ammonium chloride and partitioned between water and
EtOAc.
After concentration of the organic phase, purification was carried out with
flash
chromatography to provide 2-benzyl-oxycarbonylamino-4-phenyl-pent-4-enoic acid
ethyl
. ester. Removal of the benzyloxycarbonyl group as described above, provided
the title
compound.
..
Example G
Synthesis of 2(R~-benzyloxycarbonylamino-4-ethylhexanoic acid
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OII
I ~ O~H OH
O
Step 1
A mixture of 2-benzyloxycarbonylaminomalonic acid diethyl ester (Bladon, C. M.
J.
5. ChenZ. Soc. Perkih Trayas. 1990, 1, 1151-1158) (1.237 g), iodo-2-
ethylbutane (1.272 g) and
- lithium hydroxide (0.287 g) in N methylpyrrolidone (8 mL) was stirred for 2
days at room
temperature and then diluted with ice water. The aqueous solution was
extracted with ether
and the product purified by chromatography on silica gel to give 2-
benzyloxycarbonylamino-2-(2-ethylbutyl)malonic acid diethyl ester (0.520 g).
S.t_ ep 2
A solution of 2-benzyloxycarbonylamino-2-(2-ethylbutyl)malonic acid diethyl
ester
(0.520 g) in ethanol (5 mL) was treated with sodium hydroxide (2.91 mL, 1 N)
and then
stirred at room temperature for 8 h. The reaction mixture was diluted with
water and
acidified with HCl and the product was then extracted with ethyl acetate to
give 2-
~ benzyloxycarbonylamino-2-(2-ethylbutyl)malonic acid monoethyl ester (0.461
g).
Step 3
2-Benzyloxycarbonylamino-2-(2-ethylbutyl)malonic acid monoethyl ester was
heated at 75 °C in ethanol (5 mL) with sodium hydroxide (5 mL, 1 N) for
3 h and 2-
benzyloxycarbonyl-amino-2-(2-ethylbutyl)malonic acid was isolated by
extraction of the
acidified reaction mixture. 2-Benzyloxycarbonylamino-2-(2-ethylbutyl)malonic
acid was
heated at 103 °C for 1 h and the resulting residue was purified by
column chromatography
on silica gel to give 2(RSV-benzyloxycarbonylamino-4-ethyl hexanoic acid
(0.220 g).
Example H
~ Synthesis of 2'-chlorobiphenyl-4-carboxylic acid
O
~oH
i
I~
c~
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. Step 1
. 4-Bromobenzoic acid ethyl ester (3.91 g, 17.0 mrnol, 1.0 equiv.) was
combined with
. ~Pd tetrakis(triphenylphosphine) (0.98 g, 0.85 mmol, 0.05 equiv.), ethanol
(19 mL), and
toluene (98 mL). 'The reaction mixture was stirred for 20 min., at room
temperature. To
this was added potassium carbonate (11.74 g, 85.0 mmol, 5.0 equiv.) and 2-
chlorophenylboronic acid (4.0 g, 25.6 mmol, 1.5 equiv). The suspension was
heated to 70
°C for 6 h. The reaction mixture was diluted with ether (400 mL) and
extracted with water
(400 mL). The organic layer was washed with brine and dried over anhydrous
magnesium
sulfate. After filtering and concentration the resulting oil was purified by
flash
. chromatography (7% EtOAc/ hexanes as eluent to afford 3.16 g of 2'-
chlorobiphenyl-4-
carboxylic acid ethyl ester.
Step 2
2'-Chlorobiphenyl-4-carboxylic acid ethyl ester was dissolved in MeOH (141
mL).
To this was added sodium hydroxide (2.35 g) in water (30 mL). The solution was
stirred for
. 6 h at room temperature, then diluted with 250 mL of water, followed by
exatraction with
ether (200 mL). The aqueous layer was acidified with conc. hydrochloric acid,
extracted
with ethyl acetate (300 mL), dried then concentrated to give 2'-chloro-
biphenyl-4-
. carboxylic acid (2.81) as a white solid.
Following the procedure described in Example G above, the following starting
. materials were prepared:
2'-methylbiphenyl-3-carboxylic acid;
2'-methoxybiphenyl-3-carboxylic acid;
4-chlorobiphenyl-3-carboxylic acid;
4-chloro-2'-methyl-biphenyl-3-carboxylic acid;
- - 4-(2-methylphenyl)thiophen-2-ylcarboxylic acid;
4-(2-methoxyphenyl)thiophen-2-ylcarboxylic acid;
4-(2-chlorophenyl)thiophen-2-ylcarboxylic acid;
2-(2-methylphenyl)-3-methoxythiophen-4-ylcarboxylic acid;
. 2-(2-rnethoxyphenyl)-3-methoxythiophen-4-ylcarboxylic acid;
30~ 2-(2-methylphenyl)thiophen-5-ylcarboxylic acid;
2-(2-methoxyphenyl)thiophen-5-ylcarboxylic acid;
2-(2-methylphenyl)furan-5-ylcarboxylic acid;
2-(2-methoxyphenyl)furan-5-ylcarboxylic acid;
2-(2,6-dichlorophenyl)thiophen-5-ylcarboxylic acid;
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3,5-diphenylbenzoic acid;
3,5-di(2-methoxyphenyl)benzoic acid;
3,5-di(3-methoxyphenyl)benzoic acid;
3,5-dithiophen-3-ylbenzoic acid;
- 3,5-dipyridin-4-ylbenzoic acid;
3,5-difuran-2-ylbenzoic acid;
3,5-di(2-chlorophenyl)benzoic acid;
2,3-diphenylthiophen-5-carboxylic acid;
2,3-di(2-methoxyphenyl)thiophen-5-carboxylic acid;
~ 2,3-di(2-methylphenyl)thiophen-5-carboxylic acid;
2,3-difuran-2-ylthiophen-5~-'carboxylic acid;
2,3-di(2-chlorophenyl)thiophen-5-carboxylic acid; and
4,5-diphenylthiazol-2-ylcarboxylic acid;
Starting materials for preparing the above acid via the Suzuki coupling were
either
~ commercially available from Aldrich, Frontier, or Lancaster or they were
prepared from the
synthetic procedure described in Heterocycles, 1995, 41, 1659-1666; Biooz~g.
Med. Clzem.
1999, 7, 1559-1566.
- Example I
~ Synthesis of 2',3-dichlorobiphenyl-4-carboxylic acid
0
CI ~ off
v
CI
Step 1
3-Chloro-4-hydroxybenzoic acid methyl ester (3.0 g, 16.5 mmol, 1.0 equiv.) was
dissolved in dichloromethane (60 mL) and cooled in an ice-water bath. After
addition of
2,6-lutidine (9.6 mL), triflic anhydride (4.0 mL) was added dropwise. 'The
reaction mixture
was warmed to room temperature and subsequently stirred an additional 16 h.
The reaction
.. mixture was diluted with water and ethyl acetate. The organic layer was
washed with 1 N
HCl, saturated sodium bicarbonate, and dried over anhydrous sodium sulfate and
concentrated to give 3-chloro-4-trifluoromethane-sulfonyloxybenzoic acid which
was
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reacted with 2-chlorophenylboronic acid to give 2',3-dichlorobiphenyl-4-
carboxylic acid
methyl ester which was converted to the free acid as described above.
Utilizing the procedure described in Example I above, but substituting 3-
chloro-4-
hydroxybenzoic acid methyl ester with 6-hydroxynicotinic acid provided 2-(2-
5. ~ chlorophenyl)-pyridine-5-carboxylic acid.
Example J
Synthesis of 2-(2'-chlorobiphen-4-ylcarbonylamino)-4-phenylpent-4-enoic acid
I
O
C02H
H
I~
CI
Step 1
a-Methylstyrene was heated with N bromosuccinamide in carbon tetrachloride
to140 °C until foaming stopped. The reaction mixture was cooled to room
temperature and
filtered. a-Bromomethylstyrene and (3-bromo-a-methylstyrene were obtained by
. distillation in an 80:20 ratio and used as such in the next step.
Step 2
Sodium ethoxide was generated from sodium metal in ethanol. To this solution
was
added diethyl malonate. After stirnng the reaction mixture for 5 min., a
mixture of a-
bromomethylstyrene and [3-bromo-a-methylstyrene was added and the reaction
mixture was
heated at 50 °C for 1 h and then allowed to stir at room temperature
for 16 h. The reaction
mixture was poured into ice water and extracted with ether, dried and
concentrated. The
crude product was purified from the mixture by silica gel chromatography to
give 2-(2-
phenylallyl)malonic acid dimethyl ester.
Step 3
. 2-(2-Phenylallyl)malonic acid dimethyl ester was heated with potassium
hydroxide
. in water and ethanol mixture at 95 °C over 2 h. Ethanol was removed
and the basic layer
was washed with diethyl ether, acidified and extracted with ethyl acetate,
dried and
concentrated to give crude 2-(2-phenylallyl)malonic acid which upon heating at
145 °C
gave 4-phenylpent-4-enoic acid, which was purified by silica gel
chromatography.
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Step 4
4-Phenylpent-4-enoic acid was converted to 4-phenylpent-4-enoyl chloride as
described in Example 1 below. 4-Phenylpent-4-enoyl chloride was then converted
to 2-(2'-
chlorobiphen-4-ylcarbonylamino)-4-phenylpent-4-enoic acid by proceeding as
described in
S Example 3, Steps 2-6 described below.
Example K
Synthesis of 2(,S~-benzyloxycarbonylamino-3-pyrazol-1-ylpropionic acid
~ I
N-N
O H C02H
The title compound was prepared by treating S-benzyloxycarbonylserine-(3-
lactone
with pyrazole in acetonitrile at 60 °C for 16 h (see .I. Am. Chena.
Soc.,1985, 107, 7105-
7109).
Following the procedure described above, but substituting pyrazole with 1,2,4-
triazole and 1,2,3-triazole provided 2(.S~-benzyloxycarbonylamino-3-[1,2,4]-
triazol-1-
ylpropionic acid and 2(S~-benzyloxycarbonylamino-3-[1,2,3]-triazol-1-
ylpropionic acid
respectively.
Example L
..Synthesis of 2(S)-( tert-butoxycarbonyl)amino-1-(oxazolo[4,5-b]pyridin-2-
yl)butan-1-of
OH
N HNBoc
N
O
U
Sten 1
A mixture of 2-amino-3-hydroxypyridine (11 g, 100 mmol), triethylorthoformate
(80
, mL) and p-toluenesulfonic acid (61 mg) was heated at 140 °C for 8 h.
Excess
triethylorthoformate was removed under vacuum and oxazolo[4,5-b]pyridine was
crystalized from ethyl acetate (9 g).
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Step 2
In a clean roundbottom flask equipped with stir bar was placed oxazolo[4,5-
b]pyridine (600 mg, 5 mmol) in THF (30 mL) and the reaction mixture was cooled
to 0 °C
under NZ atomosphere. Isopropylmagnesium chloride (2 M in THF, 2.5 mL, 5 mmol
) was
added. After stirring for 1 h at 0 °C, (~-2-( tart-
butoxycarbonyl)aminobutyraldehyde ( 573
mg, 3 mmol) in THF (20 mL) was added. The ice bath was removed and the
reaction
mixture was allowed tb warm to room temperature. After 2 h, the reaction
mixture was
quenched with saturated ammonium chloride solution and concentrated to
dryness. The
residue was extracted with EtOAc, then washed with brine, dried with anhyd.
MgS04,
10. . filtered and concentrated. The crude product was purified by
chromatograph to yield 383
mg of the desired compound.
Hl NMR (DMSO-d6): ~ 8.42 (m, 1H), 8.18 (m, 1H), 7.3(m, 1H), 6.8- 6.6 (dd, d,
1H,
OH, diastereomer), 6.3- 6.02 (d, d, 1H, NH, diastereomer), 4.82- 4.5 (m,m, 1H,
diastereomer), 1.8-1.3 (m, 2H), 1.2-1.05 (s,s, 9H, diastereomer), 0.89 (m,
3H). MS: 306.2
(M-1), 308.6 (M+1).
Example M
Synthesis of 2(S~-(tart-butoxycarbonyl)amino-3-thiazol-2-ylpropionic acid
S
--N
.. ~ ~ OII
O~N C02H
20~ ~ H
To 2-tart-butoxycarbonylamino-3-thiazol-2-yl-propionic acid methyl ester (500
mg,
. ~ 1.75 mmol) in a mixture of acetonitrile (6 mL) and 0.2 M aqueous NaHC03
(12 mL) was
added Alcalase (2.4 L, 0.08 mL), and the solution was stirred vigorously at
room
temperature for about 2.5 h. The reaction mixture was then evaporated at 30
°C to remove
acetonitrile, and the aqueous residue was washed with ether. The aqueous phase
was
acidified with 6 N HCl to pH 3 and the solution was extracted with ethyl
acetate. The
combined organic layers were then dried and evaporated to yield 2(S~-tert-
butoxycarbonylamino-3-thiazol-2-yl-propionic acid (204 mg).
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Example 1
Synthesis ofN [1(S)-benzoxazol-2-ylcarbonylpropyl]-2(S)-(2'-chlorobiphen-4-
. ylcarbonylamino)-3-(2,6-difluorophenyl)propionamide
5. ~ (compound 1 )
F
O H O
N~O
~N
O \ N
CI
Ste~l
A solution of (SS, 6R)-4-(tent-butyoxycarbonyl)-5,6-Biphenyl-2,3,5,6-
tetrahydro-4H
1,4-oxazine-2-one (10.59 g, 0.03 mol) and 2,6-difluorobenzyl bromide (7.038 g,
0.034 mol)
in tetrahydrofuran (150 mL) was cooled to -60 °C and then treated with
sodium
hexamethyldisilazane (32 mL of 1N in tetrahydrofuran) by slow addition over 20
min. The
reaction mixture was stirred at -67 °C for 105 min., and then poured
into cold water. The
~ product was extracted with ethyl acetate. The extracts were dried and
concentrated to 120
mL and cooled to 0 °C. Filtration in two crops gave (3S, SS, 6R)-4-
(tent-butyloxycarbonyl)-
3'=(2,6-difluorophenylmethyl)-5,6-Biphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazine-2-
one (8.898
g, 62%).
Step 2
.. A solution of (3S, SS, 6R)-4-(tent-butyloxycarbonyl)-3-(2,6-
difluorophenylmethyl)-
5,6-Biphenyl-2,3,5,6-tetrahydro-4H 1,4-oxazine-2-one (7.282 g, 0.0152 mol) in
methylene
chloride (150 mL) was cooled to 0 °C and treated with trifluoroacetic
acid (15 mL) and then
stirred at room temperature for 4.5 h. The reaction mixture was cooled to 0
°C and treated
with triethylamine (27.8 mL). The reaction mixture was then concentrated at
reduced
w pressure, diluted with cold water and the product extracted with ethyl
acetate to give (3S,
SS, 6R)-3-(2,6-difluorophenylmethyl)-5,6-Biphenyl-2,3,5,6-tetrahydro-4H-1,4-
oxazine-2-
one (5.86 g) as an oil which was used in the next step without purification.
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Step 3
A solution of (3S, SS, 6R)-3-(2,6-difluorophenylmethyl)-5,6-diphenyl-2,3,5,6-
tetrahydro-4H 1,4-oxazine-2-one (5.86 g, 0.152 mol) in tetrahydrofuran (25 mL)
and
' methanol (25 mL) was hydrogenated in the presence of palladium chloride
(0.317 g) at 55
5' psi for 16 h. More (0.100 g) palladium chloride was added to the reaction
mixture and the
hydrogenation continued for an additional 3 h. The catalyst was removed by
filtration, the
solvents were removed at reduced pressure and the residue was acidified with
1N aqueous
hydrochloric acid. After washing with ethyl acetate the aqueous layer was
neutralized to pH
6.9 at 0 °C with 1N sodium hydroxide and then evaporated. The resulting
solid was slurried
and filtered with methanol (50 mL) twice. Cooling of the methanolic extracts
on ice then
gave 2(S~-(2,6-difluorophenyl)alanine (1.189 g) as white needles.
Step 4
2'-Chloro-4-biphenylcarboxylic acid (2.77 g, 11.9 mmol) was suspended in ethyl
acetate (36 mL). A single drop ofN,N dimethylformamide was added and the
suspension
1 ~ cooled in an ice bath. Oxalyl chloride was added dropwise over 5 min., the
bath removed
and the resulting solution stirred for an additional 20 min. The solvent
removed ira vacuo
and the resulting 2'-chloro-4-biphenylcarbonyl chloride was used immediately
without
purification.
Step 5
- 2,6-Difluorophenylalanine (2.4 g, 11.9 mmol) was dissolved in 2 N NaOH (11.
9
rraL) and dioxane (10 mL) and the solution was cooled in an ice/water bath. A
solution of
2'-chloro-4-biphenylcarbonyl chloride in tetrahydrofuran (12 mL) was added
concurrently
with 2 N NaOH solution (5.9 mL) over 20 min. The ice bath was removed and the
reaction
mixture was stirred an additional 45 min., after which it was acidified to pH
4 with
~ concentrated HCI. The product was extracted with dichloromethane and the
ethereal layer
was concentrated to give 2-(2'-chlorobiphen-4-ylcarbonylamino)-3-(2,6-
difluorophenyl)propionic acid (3.1 g) which was used in the next step without
further
purification.
Step 6
~ ~ To a solution of 2(S~-Boc-aminobutanol in dichloromethane (10 vol) and
water (7
vol) were added at 20 °C TEMPO (0.01 equiv.), sodium bromide (1 equiv.)
and sodium
hydrogen carbonate (3 equiv.). The reaction mixture was stirred at 0 °C
and diluted bleach
- ~ .('1.3 equiv., 9 vol) was added over 40 min. The reaction mixture was
stirred for 30 min.,
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and then quenched with aq. thiosulfate. After decantation, and extractions
. ~ (dichloromethane), the organic phase was washed with brine, dried and
concentrated ira
vacuo to dryness, giving 77% of 2(S~-( tent-butoxycarbonyl)amino-butyraldehyde
as a low-
rnelting solid.
. To a solution of 2(,S~-(tert-butoxycarbonyl)aminobutyraldehyde (5.00 g) in
toluene
(5 vol) was added a solution of Grignard reagent of benzoxazole (prepared at -
5 °C from
~, , 1.1 equiv. benzoxazole and 1.1 equiv. isopropylmagnesium chloride in THF-
toluene 1/l,
total 6.5 vol) was added over 30 min. at -5 °C. The reaction mixture
was stirred for 1 h at 0
°C, then 2.5 h at r.t. Quenching with 5% acetic acid(aq.), washings
with 5% Na2C03(aq.),
then brine and concentration to dryness gave crude 2(,S')-(tert-
butoxycarbonyl)amino-1-benzoxazol-2-yl- butan-1-of in a quantitative yield.
The residue
was diluted with toluene (12 vol), and Florisil° (6 p.) was added. The
slurry was filtered on
a pad of Florisil° (6 p). Elution by toluene (40 vol) removed the non-
polar impurities.
Toluene- ethyl acetate (8/2) desorbed the 2(~-(tert-butoxycarbonyl)-
amino-1-benzoxazol-2-ylbutan-1-of (60-65% yield; red resin).
2(~-(tert-butoxycarbonyl)amino-1-benzoxazol-2-ylbutan-1-of (2.5 g) was treated
with trimethylchlorosilane (1.4 equiv.) in isopropanol (4 vol) for 5 h at 50
°C.
Concentration of the reaction mixture to dryness followed by addition of
acetone (3 vol)
afforded 2(S~-amino-1-benzoxazol-2-yl-butan-1-of hydrochloride salt as a
crystalline
~ product (0.76 g).
Step 7
2-(2'-Chlorobiphen-4-ylcarbonylamino)-3-(2,6-difluorophenyl)propionic acid
(5.1 g.,
12.26 mmol) was dissolved in acetonitrile (40 mL). HBTU (5.46 g., 14.41 mmol),
2(S)-
amino-1-benzoxazol-2-ylbutanol (2.97 g., 14.41 mmol), and N methylmorpholine
(4.34 g, 42.9
26. mmol) was added. The resulting solution was stirred at ambient temperature
for 16 h. The
reaction mixture was diluted with ethyl acetate (200 mL) and saturated
ammonium chloride
(30 mL), then stirred an additional 30 min. The organic layer was removed and
the residue
was extracted several times with ethyl acetate. The combined organic layers
were washed with
. . saturated sodium bicarbonate, saturated sodium chloride, and then dried
over anhydrous
. ~ ~ magnesium sulfate. The solvent was removed and the resulting solid was
purified by column
chromatography using 50% ethyl acetate/hexanes as eluent to give N [2(,S~-1-
benzoxazol-2-yl-
1-hydroxybutan-2-yl~-2-(2'-chlorobiphen-4-ylcarbonylamino)-3-(2,6-
difluorophenyl)propionamide (2.1 g) as a mixture of diastereomers.
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Step ~
N [2(~-1-Benzoxazol-2-yl-1-hydroxybutan-2-yl]-2-(2'-chlorobiphen-4-
ylcarbonylamino)-3-(2,6-difluorophenyl)propionamide (2.1 g, 3.48 mmol) was
dissolved in
dichloromethane (30 mL). Dess-Martin periodinane (2.21 g, 5.22 mmol) was added
and the
reaction mixture was stirred the reaction for 45 min. NazS203 (20 mL, 0.26 M)
in saturated
sodium bicarbonate and ethyl acetate (200 mL) was added and the reaction
mixture was stirred
for an additional 30 min. The organic layer was removed and the residue
remaining was
washed several times with ethyl acetate. The combined organic layers were
washed with
saturated sodium bicarbonate, saturated sodium chloride, then dried over
anhydrous
10. magnesium sulfate. The solvent was removed to give N [1(S~-benzoxazol-2-
ylcarbonylpropyl]-2(S)-(2'-chlorobiphen-4-ylcarbonylamino)-3-(2,6-
difluorophenyl)-
propionamide (2.1 g) as a white solid (a mixture of diastereomers approx.
8:1).
1H NMR (400MHz) (CDC13): 8 0.97 (t, J 6.97 Hz, 3H), 1.95 (m, 1H), 2.17 (m,
1H),
3.28 (m, 2H), 4.98 (m, 1H), 5.60 (m, 1H), 6.81 (t, J 8.0 Hz, 2H), 6.90 (d, J
8.8 Hz, 2H),
7..10 (t, J 8.0 Hz, 1H), 7.21 (d, J 7.6 Hz, 1H), 7.32 (m, 3H), 7.50 (m, 4H),
7.57 (t, J 6.0 Hz,
1H), 7.68 (d, .I-- 8.0 Hz, 1H), 7.79 (d, J 6.8 Hz, 2H), 7.88 (d, J BHz, 1H).
Proceeding as described in Example 1 above, but substituting appropriate
starting
materials, the following compounds of the present invention were prepared in
Table 1:
Compound 2:
~, N [1(S7-benzoxazol-2-ylcarbonylpropyl]-2(RS~-(2'-chlorobiphen-4-
ylcarbonylamino)-3-(2,6-difluorophenyl)propionamide; 1H NMR (DMSO-d6): 8 8.69
(t, J
7.6Hz, 1H), 8.59 (J 8Hz, 1H), 7.98-7.2 (m, 12H), 6.97 (q, 3H), 5.1-4.9 (m,
1H), 4.9-4.8
(m, 1H), 3.24-2.9 (m, 2H), 1.95 (m, 1H), 1.7 (m, 1H); 0.88- 0.83(t, J BHz,
3H); MS: 600.4
(M-1), 602.4 (M+1).
Compound 3:
N [1(S~-benzoxazol-2-ylcarbonylpropyl]-2(R~-(2,3-diphenylthiophen-2
ylcarbonylamino)-3-(2,6-difluorophenyl)propionamide; 1H NMR (DMSO-d6): 8 8.8-
8.7
(rn, 2H), 8.0-6.9 (m, 18H), 5.18 (m, 1H), 4.85 (m, 1H), 3.2-2.9 (m, 2H), 1.95
(m, 1H), 1.70
(m, 1H); 0.93= 0.81(t, J 7.6Hz, 3H); MS: 648.4 (M-1), 650.4 (M+1).
~ Compound 5:
N [1(R~-benzoxazol-2-ylcarbonylbutyl]-2(R~-(2'-chlorobiphen-4-
ylcarbonylamino)-3-(2,6-difluorophenyl)propionamide; 1H NMR(DMSO-d6): b 8.7-
8.54
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(m, 2H), 7.88-7.76 (m, 13H), 7.04-6.92 (q, 2H), 5.3-5.2 (m, 1H), 4.85 (m, 1H),
3.15-2.95
(m, 2H), 1.9 (m, 1H), 1.65 (m, 1H), 1.4-1.1 (m, 2H), 0.8 (m, 3H); MS: 614.2 (M-
1).
Compound 7:
N [ 1 (RSV-benzoxazol-2-ylcarbonylpentyl]-2(RS~-(2'-chlorobiphen-4-
. ylcarbonylamino)-3-(2,6-difluorophenyl)propionamide; 1H NMR (DMSO-d6): b
8.75-8.5
. (m, 2H), 8.0-7.15 (m, 12H), 6.95 (q, 2H), 5.3 (m, 1H), 4.9 (m, 1H), 3.23-
2.9 (m, 2H), 2.2-
1.1 (m, 6H), 0.85 (m, 3H); MS: 628.6 (M-1), 630.4 (M+1).
Compound 19:
N [1(S~-benzoxazol-2-ylcarbonylpropyl]-2(S~-(2,3-diphenylthiophen-5-
10~ ylcarbonylamino)-3-(2,6-difluorophenyl)propionamide; 1H NMR (DMSO-d6) 8
8.79-8.71
(m, 2H), 7.95 (d, J 8.4Hz,lH), 7.94, (s, 1H), 7.89 (d, J 8.4Hz, 1H), 7.62 (t,
J--8.4Hz, 1H),
7.50 (t, J 8.4Hz, 1H), 7.38-7.22 (m, 11H), 7.05-6.95 (m, 2H), 5.23-5.18 (m,
1H), 4.88-4.82
(m, 1H), 3.22-3.15 (m, 1H), 3.04-2.97 (m, 1H), 2.04-1.90 (m, 1H), 1.80-1.68
(m, 1H), 0.95
(t, J 7.2Hz, 3H). MS: 650 (M+H)+.
Compound 40:
N [1(RSV-benzoxazol-2-ylcarbonylpropyl]-2(R~-(4-phenoxyphenylcarbonylamino)-
3-(2,6-difluorophenyl)propionamide; Hl NMR (DMSO-d6): 8 8.7-8.59 (q, 1H), 8.55-
8.45
(q, 1H), 8.1-6.95 (m, 16H), 5.15-5.05 (m, 1H), 4.95-4.86 (m, 1H), 3.25-3.1 (m,
1H), 3.05-3
(m, 1H), 2.05-1.9 (m, 1H), 2.9-1.65 (m, 1H), 1.0-0.8 (m, 3H). MS: 582.4 (M-1),
584.4
(M+1 ).
Compound 52:
N [1(S~-benzoXazol-2-ylcarbonylpropyl]-2-(2'chlorobiphen-4-ylcarbonylamino)-
acetamide; Hl NMR (DMSO-d6): 8 8.85-8.8 (t, J =6.4 Hz, 1H), 8.64-8.62 (d, J
6.4 Hz, ,
1H), 8.04-7.44(m, 12H), 5.8-5.4 (m, 1H), 4.1-3.9(m, 1H), 2.1-2.0 (m, 1H), 1.85-
1.7 (m,
25. ~ 1H), 1.02(t, J 7.2 Hz, 3H). MS: 474.2 (M-1), 476.4 (M+1).
Example 2
Synthesis of N [ 1 (,S~-benzoxazol-2-ylcarbonylpropyl]-2(S')-(2'-chlorobiphen-
4-ylcarbonyl-
amino)-4(~-phenylpentamide andN [1(,S~-benzoxazol-2-ylcarbonylpropyl]-2(R)-(2'-
~ chlorobiphen-4-ylcarbonylamino)-4(S~-phenylpentamide
(compounds 4 and 12)
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\ \
I/ I/
O H O and O
N O N~ ~ ~O
I\ H ~ I\ H
\ / O ~ N / ~ \ / O ~ N ~
( / CI I / CI
Step 1
2(S~-Phenylpropanol was converted to 1-trifluoromethanesulfonyloxy-2(~-
phenylpropane by the procedure given in Org. Syn. Col. Vol. VIII, p 126.
Step 2
6-Oxo-(2R,3f)-diphenylmorpholine-4-carboxylic acid benzyl ester was converted
to
6-oxo-(2R,3..S7-diphenyl-5-(2S-phenylpropyl)morpholine-4-carboxylic acid
benzyl ester
which was then converted to a mixture of 2(R)-amino-4(S~-phenylpentanoic acid
and 2(S7-
amino-4(,S7-phenylpentanoic acid by the methods of Williams, et al., Methods
in Molecular
Medicine, in Peptidomirnetics Protocols; Ed. Kazmierski, W.M. Humana Press
Inc.:
Totowa, N. J.; Vol. 23, p 339-356 and J. Am. Chem Soc. 1991, 113, 9276-926,
respectively.
Step 3
1 ~ . A mixture of 2(R)-amino-4(,S~-phenylpentanoic acid and 2(S~-amino-4(~-
phenylpentanoic acid was converted to N [1(,S~-benzoxazol-2-ylcarbonylpropyl]-
2(S~-(2'-
chlorobiphen-4-ylcarbonyl-amino)-4(~-phenylpentamide and N [1(S~-benzoxazol-2-
ylcarbonylpropyl]-2(R)-(2'-chlorobiphen-4-ylcarbonylamino)-4(S~-
phenylpentamide by
following the procedure described in Example 1 above. The pure diastereomers
were
20. separated by silica gel chromatography using 2-5% diethyl ether in
dichloromethane.
2(~-Amino-4(~-phenylpentanoic acid can also be prepared as a single (S,S7
diastereomer from 6-oxo-(2R,3S)-diphenylmorpholine-4-carboxylic acid benzyl
ester as
described above by adding all reagents slowly enough to maintain an internal
reaction
temperature of less than -65 °C.
25 N [1(f)-Benzoxazol-2-ylcarbonylpropyl]-2(~-(2'-chlorobiphen-4-ylcarbonyl-
. amino)-4(S~-phenylpentamide; 1H NMR (CDC13): 8 0.93 (t, .I--- 9 Hz, 3H),
1.29 (d, J 6 Hz,
3H), 1. 93 (rn, 1H), 2.17 (m, 3H), 2.93 (m, 1H), 4.57 (m, 1H), 5.57 (m, 1H),
6.70 (d, J-- 9
Hz, 1H), 6.77 (d, J 9Hz, 1H), 7.17 (m, 1H), 7.30 (m, 7H), 7.47 (m, 4H), 7.53
(m, 1H), 7.67
(m, 3H), and 7.~7 (d, J 9Hz, 1H). MS: 594.5 (M+1); 616.4 (M+23).
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N [1(S)-Benzoxazol-2-ylcarbonylpropyl]-2(R)-(2'-chlorobiphen-4-yl-
carbonylamino)-4(S)-phenylpentamide. 1H NMR (CDC13): 8 0.93 (t, J 9 Hz, 3H),
1.33 (d,
.>= 6 Hz, 3H), 1.87 (m, 1 H), 2.17 (m, 1 H), 2.27 (m, 2H), 3.00 (m, 1 H), 4.70
(m, 1 H), 5.57
(m, 1H), 6.47 (d, J 9 Hz, 1H), 7.07 (d, .l 9Hz, 1H), 7.20 - 7.33 (m, 8H), 7.40
- 7.57 (m,
7H), 7.63 (d, J-- 9Hz, 1H), and 7.80 (d, J 9Hz, 1H). MS: 616.4 (M+23).
Example 3
Synthesis of N [ 1 (S)-benzoxazol-2-ylcarbonylpropyl]-2(S)-(2'-chlorobiphen-4-
ylcarbonyl-
amino)-4-ethylhexanoamide
. (compound 24)
O H O
N~O
~N
/ H O ~ N
/
CI
Step 1
. ~ A solution of 4-ethylhexanoic acid (prepared by the method described in P.
Daud,
G. Kaufinan, P.Kaufinan, Y. Paik, Tet. Lett., 1985, 26, 2279-2282) (11.63 g)
in ethyl acetate
(150 mL) and dimethyl formamide (2 drops) was treated with oxalyl chloride
(10.5 mL) at 0
°C and then stirred at room temperature for 50 min. The solvents were
evaporated to give
4-ethylhexanoyl chloride (11.75 g).
. , Step 2
A solution of 4(S)-phenylrnethyl-2-oxazolidone (5.316 g) in THF (60 mL) was
cooled to -65 °C and treated with rz-butyllithium (20 mL, 1.6 M) over
20 min. A solution
of 4-ethylhexanoyl chloride (20.04 g) in THF (5 mL) was added at -65 °C
over 20 min.
After 30 min., the reaction mixture was quenched in ice water and the product
extracted
with ethyl acetate to give 3-(4-ethylhexanoyl)-4(S)-phenylmethyl-2-oxazolidone
(8.78 g).
Ste~3
3-(4-Ethylhexanoyl)-4(S)-phenylmethyl-2-oxazolidone was converted to 3-(2S-
azido-4-ethylhexanoyl)-4(S)-phenylmethyl-2-oxazolidone using potassium
hexarnethyldisilazide and trisyl azide as described by D.A. Evans, T.C.
Britton, J. A.
- Ellman, R.L. Dorow, J. Arn. Chem. Soc., 1990, 112, 4011-4030.
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Step 4
3-(2S-Azido-4-ethylhexanoyl)-4(~-phenylmethyl-2-oxazolidone (0.20 'g) in
I . methanol (6 rnL) was treated with 5% Pd / C (70 mg) and the hydrogenated
at 1 atm. When
the reaction was complete the reaction mixture was filtered and the methanol
evaporated to
, give 3-(2S-amino-4-ethylhexanoyl)-4(~-phenylmethyl-2-oxazolidone.
Step 5
3-(2(S~-Amino-4-ethylhexanoyl))-4(,S~-phenylmethyl-2-oxazolidone was dissolved
-. xn acetonitile and treated with HBTU (285 mg), 2'-chloro-4-biphenyl
carboxylic acid (175
mg) and N methylmorpholine (0.22 mL). After stirring at room temperature for
24 h the
- reaction mixture was diluted with water and the product extracted with ethyl
acetate and
purified by chromatography on silica gel to give 3-[2(S~-(2'-chlorobiphen-4-
ylcarbonylamino)-4-ethylhexanoyl)]-4(S~-phenylmethyl-2-oxazolidone (0.128 g).
Step 6
3-[2(~-(2'-Chlorobiphen-4-ylcarbonylamino)-4-ethylhexanoyl)]-4(~-
15. phenylmethyl-2-oxazolidone (0.100 g) in THF (5 mL) was cooled on ice and
treated with
. water (1.25 mL), hydrogen peroxide (30% 1.95 mL) and lithium hydroxide
(0.0010 g). The
reaction mixture was stirred at room temperature for 90 min. The reaction
mixture was
quenched with aqueous sodium sulfite and the product isolated from the
acidified aqueous
layer to give 2(S7-(2'-chlorobiphen-4-ylcarbonylamino)-4-ethylhexanoic acid
(0.032 g).
20_ Step 7
2(~-(2'-Chlorobiphen-4-ylcarbonylamino)-4-ethylhexanoic acid in methylene
chloride (2 mL) was treated with 2(S~-amino-1-benzoxazol-2-ylbutanol (25 mg),
EDC (26
mg), HOBt (17 mg) and N-methylrnorpholine (0.2 mL). The reaction mixture was
stirred at
room temperature for 35 minutes and then worked up with ethyl acetate and
water to give
25 N [2(~-1-benzoxazol-2-yl-1-hydroxybutan-2-yl]-2-(2'-chlorobiphen-4-
ylcarbonylamino)-
4-ethylhexanoamide (21 mg).
St_ ep ~
N [2(~-1-benzoxazol-2-yl-1-hydroxybutan-2-yl]-2-(2'-chlorobiphen-4-
ylcarbonylamino)-4-ethylhexanoamide (16 mg) was dissolved in methylene
chloride (1.5
30. ~ mL) and treated with Dess-Martin periodinane (16 mg). After stirring 20
min., at room
temperature the reaction mixture was quenched with aqueous sodium thiosulfate
and the
. product isolated by extraction with ethyl acetate to give the title compound
(8 mg).
Example 4
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Synthesis ofN [1(~-benzoxazol-2-ylcarbonylpropyl]-2(S~-(2'-chlorobiphen-4-
ylcarbonylamino)-cyclohexylacetamide
(compound 25)
. H O
N~O
~ N
Step 1
To a stirred mixture of tent-butoxycarbonylaminocyclohexylacetic acid (250 mg,
0.97 mmol), 2-amino-1-benzooxazol-2-yl-butan-1-of TFA salt (0.97 mmol), and
HOBt (183
mg, 1.2 mmol) in acetonitrile (5 mL) was added EDC (290 mg, 1.5 mrnol) and N
methylmorpholine (0.45 mL) at room temperature. After stirnng for 14 h, the
reaction
mixture was extracted with ethyl acetate. The organic layer was washed with
saturated
NaHC03, brine, dried with MgS04 and concentrated to yield f [1-(benzoxazol-2-
ylhydroxymethyl)propylcarbamoyl]-cyclohexylmethyl}-carbamic acid tent-butyl
ester (400
~ mg) which was used in the next step without further purification.
S'ten 2
f [1-(Benzoxazol-2-ylhydroxymethyl)propylcarbamoyl]cyclohexylmethyl}carbamic
acid tent-butyl ester (400 mg, 0.9 mmol) and methylene (5 mL) were mixed and
TFA (1
~. . ~) was added at room temperature. After stirring for 1 h, the solvent and
excess TFA
20.' were removed under vacuum to 2-amino-N [1-(benzoxazol-2-
ylhydroxymethyl)propyl]-2
cyclohexylacetamide TFA salt.
. ~ Step 3
To a stirred mixture of 2-amino-N [1-(benzoxazol-2-ylhydroxymethyl)propyl]-2-
. . cyclohexylacetamide TFA salt ( 0.48 mmol) made as above, 2'-chloro-
biphenyl-4-
, ~ ~ carboxylic acid (111 mg, 0.48 mmol) and HOBt (88 mg, 0.58 mmol) in MeCl2
(5 mL) was
added EDC (139 mg, 0.72 mmol) and N methylmorpholine (0.32 mL) at room
temperature.
' After stirring for 14 h, the reaction mixture was extracted with ethyl
acetate. The organic
. layer was washed with saturated NaHC03, brine, dried with MgS04 and
concentrated to
yield 2'-chlorobiphenyl-4-carboxylic acid {[1-(benzoxazol-2-yl-hydroxy-
methyl)propylcarbamoyl]cyclohexylmethyl}-amide (187 mg).
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Step 4
2'-Chlorobiphenyl-4-carboxylic acid {[1-(benzoxazol-2-yl-hydroxy-methyl)propyl-
carbamoyl]cyclohexylmethyl}amide was dissolved in MeCl2 (5 mL) and the
solution was
treated with Dess-Martin periodinane (288 mg, 0.68 mmol) at room temperature.
After
stirnng for 1 h, 5 rnL of saturated NaZS203-NaHC03 were added. After a further
0.5 h, the
reaction mixture was extracted with ethyl acetate, washed with brine, dried
with MgS04 and
concentrated. The residue was purified with silica gel column chromatography
to yield
100mg of the title compound.
1H NMR (DMSO-d6): ~ 8.7 (d, J 12.8Hz, 1H), 8.28 (d, J 8.4Hz, 1H), 8.0-7.8 (m,
4H), 7.65-7.38 (m, 8H), 5.17 (m, 1H), 4.4 (t, 1H), 2.0 (m, 1H), 1.8-1.5 (m,
7H), 1.2-1.0 (m,
SH), 0.98 (t, J 7.2Hz, 3H). MS: 558.2 (M+1), 580.4 (M+Na).
Compound 15:
Following the procedure described in Example 4 above, but substituting 2-amino-
1-
benzoxazol-2-ylbutan-1-of with 2-amino-1-(oxazolo[4,5-b]pyridin-2-yl)butan-1-
of provided
- N [1-(S)-oxazolo[4,5-b]pyridin-2-ylcarbonylpropyl]-2(S~-(2'-chlorobiphen-4-
ylcarbonylamino)-cyclohexylacetamide. 1H NMR (DMSO-db): 8 8.79 (d, J 5.2Hz,
1H), 8.7
(m, 1H), 8.86 (m, 2H), 8.28 (d, J 8.4Hz, 1H), 7.86 (m, 1H), 7.65-7.6 (rn, 1H),
7.6-7.55 (m,
1H), 7.5-7.38 (m, SH), 5.12 (m, 1H), 4.4 (t, J 8.4Hz, 1H), 2.1-1.9 (m, 1H),
1.85-1.5 (m,
7H), 1.2-1.1 (m, SH), 0.99 (t, J 6.4Hz, 3H). MS: 559.3 (M-1), 581.5 (M+Na).
20- Compound 22:
Following the procedure described in Example 4 above, but substituting 2-amino-
1-
benzoxazol-2-yl-butan-1-of with 2-amino-1-(oxazolo[4,5-b]pyridin-2-yl)butan-1-
of and 2'-
chlorobiphenyl-4-carboxylic acid with 2',3-dichlorobiphenyl-4-carboxylic acid
provided N
~~ [1(R,S~-oxazolo[4,5-b]pyridin-2-ylcarbonylpropyl]-2(R~S)-(2',3-
dichlorobiphen-4-
. ylcarbonylamino)-cyclohexylacetamide. 1H NMR (DMSO-d6): S 8.87 (d, J 4.8Hz,
1H),
8.29 (d, J--8.8Hz, 1H), 7.88-7.84 (m, 2H), 7.7-7.3 (m, 6H), 5.03 (m, 1H), 4.4
(t, J 8.4Hz,
1H), 2.95 (q, J=6Hz, 2H), 2-1 (m, 15H), 1.28 (t, J--7.6Hz, 3H), 0.898 (t, J
5.6Hz, 3H). MS:
551.4 (M-1), 573.4 (M+1).
Compound 26:
Following the procedure described in Example 4 above, but substituting 2-amino-
1
benzoxazol-2-ylbutan-1-of with 2-amino-(2-ethyl-[1.3.4]-oxadiazol-5-yl)pentan-
1-of
- providedN [1-(S')-(2-ethyl-[1.3.4]-oxadiazol-5-ylcarbonyl)butyl]-2(~-(2'-
chlorobiphen-4-
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ylcarbonylamino)-cyclohexylacetamide. 1H NMR (DMSO-d6): 8 9-7.2 (m, 12H), S.1-
5 (m,
1H), 4.6-4.2 (m, 1H), 2.1-2 (m, 1H), 1.9-0.9 (m, 15H). MS: 593.3 (M+1), 615.3
(M+Na).
Example 5
Synthesis ofN [1-(~-benzoxazol-2-ylcarbonylpropyl]-2(R~-(2'-chlorobiphen-4-
ylcarbonylamino)thiazol-2-ylpropionamide
(compound 17)
S
O H O
N~O
_ [N
O ~ N ~
CI
~ Step 1
To a solution of 2-amino-3-thiazol-2-ylpropionic acid (100 mg, 0.58 mmol) in
the
mixture of methanol (1 mL) and benzene (5 mL), was added
(trimethyl)diazomethane (2 M
solution in hexane, 0.76 mL) at room temperature. After 2 h, the solvent was
removed
under vacuum. The residue was used in the next reaction without further
purification.
15- Step 2
To a stirred solution of 2-amino-3-thiazol-2-ylpropionic acid methyl ester in
methylene chloride (5 mL) was added 2'-chlorobiphenyl-4-carboxylic acid (132
mg, 0.57
mmol), HOBt (105 mg, 0.68 mmol), and then EDC (165 mg, 0.86 mmol) and N
methylmorpholine (0.3 mL) at room temperature. After stirnng for 14 h, the
reaction
mixture was extracted with ethyl acetate. The organic layer was washed with
saturated
NaHCO3, brine, dried with MgS04 and concentrated to yield 2-(2'-chlorobiphenyl-
4-
carbonylamino)-3-thiazol-2-ylpropionic acid methyl ester.
Step 3
2-(2'-Chlorobiphenyl-4-carbonylamino)-3-thiazol-2-ylpropionic acid methyl
ester
- was dissolved in MeOH (3 mL) and then aq. NaOH was added (1 N, 0.68 mL) at
room
temperature. After stirnng for 1 h, the reaction mixture was acidified with 1
N HCl to pH 2.
The product was extracted with ethyl acetate and washed with brine. After
drying with
MgS04, the solvent was removed under vacuum and the product was crystallized
from
ethyl acetate and hexane to yield 176 mg of 2-(2'-chlorobiphenyl-4-
carbonylamino)-3-
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thiazol-2-yl-propionic acid which was then converted to the title compound by
following
the procedure described in Example 1 above.
1H NMR (DMSO-d6): ~ 8.86 (m, 2H), 7.96 (m, 1H), 7.88 (m, 2H), 7.69 (t, J
2.4Hz,
1H), 7.65-7.35 (m, lOH), 5.22 (m, 1H), 5.0 (m, 1H), 3.6-3.4 (m, 2H), 2.0 (m,
1H), 1.77 (m,
1H), 0.98 (m, 3H). MS: 571.2(M-1), 573 (M-1), 595.2 (M+Na).
Example 6
Synthesis of N [ 1 (,S')-benzoxazol-2-ylcarbonylpropyl]-2(,S')-[2-(2-
chlorophenyl)pyridin-5-
ylcarbonylamino)-cycloheptylacetamide
(compound 20)
O H O
N~O
~N
N~ H O ~ N
CI
The title compound was prepared following the procedure described in Example 3
above, but substituting 2'chloro-4-biphenylcarboxylic acid with 2-(2-
chlorophenyl)pyridinecarboxylic acid and 4-ethylhexanoic acid with 2-
cycloheptylacetic
. . acid.
1H NMR (DMSO-d6): 8 9.05 (d, J l.2Hz, 1H), 8.09 (dd, J 2.4Hz, J 8Hz, 1H),
7.816 (d, J--8Hz, 1H), 7.68 (d, J 7.6Hz, 1H), 7.6-7.2 (m, 7H), 8.864 (d, J
8Hz, 1H), 6.592
(d, J 8Hz, 1H), 5.584 (m, 1H), 4.6 (t, J 7.4Hz, 1H), 2.25-1.2 (m, 15H), 0.956
(t, J--7.2Hz,
~H). MS: 572.2(M-1)~ 573.4 (M-1), 595.5 (M+Na).
Example 7
Synthesis of N [ 1 (~-benzoxazol-2-ylcarbonylpropyl]-2(,S~-[2-(2-
chlorophenyl)pyridin-1-yl-
carbonylamino]-4(S~-phenylpentamide
(compound 21)
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O H O
N~O
IN
\ I N~ H O ~ N
/
CI
Proceeding as described in Example 1 above, but substituting 2,6-
difluorophenylalanine with 2(f)-amino-3(S~-phenylpentanoic acid and 2'-chloro-
4-
~ biphenylcarbonyl chloride with 2-(2-chlorophenyl)pyridin-5-ylcarbonyl
chloride provided
2-[2-(2-chlorophenyl)pyridin-5-ylcarbonyl-amino]-4(,S')-phenylpentanoic acid
which was
then converted to N [1(S~-benzoxazol-2-ylcarbonylpropyl]-2(S~-[2-(2-
chlorophenyl)pyridin-
1-ylcarbonylamino]-4(S~-phenyl-pentamide. MS 596.1 (M+1).
Analytical data for other compound of the Invention is as follows:
Compound 4:
N [1(~-benzoxazol-2-ylcarbonylpropyl]-2(~-(2'-chlorobiphen-4-ylcarbonylamino)-
4(S~-phenylpentamide. 1H NMR (CDC13): 8 7.90 (m, 1H), 7.71 (m, 3H), 7.51 (m,
SH),
7.14-7.40 (m, 8H), 6.73 (m, 1H), 6.64 (m, 1H), 5.62 (m, 1H), 4.58 (m, 1H),
2.98 (m, 1H),
2.21 (m, 3H), 1.92 (m, 1H), 1.33 (m, 3H), 0.99 (m, 3H). MS: 592.2 (M-1), 594.3
(M+1).
Compound 8:
N [1(S~-oxazolo-[4,5-b]pyridin-2-ylcarbonylpropyl]-2(,S')-(2'-chlorobiphen-4-
ylcarbonylamino)-3-(2,6-difluorophenyl)propionamide. MS: 603.4 (M+1), 601.5 (M-
1).
Compound 9:
.' N [1(S~-oxazolo-[4,5-b]-pyridin-2-ylcarbonylpropyl]-2(R~-(2'-chlorobiphen-4-
yl-
. carbonylamino)-3-(2,6-difluorophenyl)propionamide. MS: 603.4 (M-1), 605.2
(M+1).
. , Compound 10:
w N [1(~-(2-pyridin-3-yl-[1,3,4]-oxadiazol-5-ylcarbonyl)pentyl]-2(R~-(2'-
chlorobiphen-4-ylcarbonylamino)-3-(2,6-difluorophenyl)propionamide. MS: 656.4
(M-1),
658.6 (M+1).
25~ Compound 11:
- N [1(,S~-(2-pyridin-4-yl-[1,3,4]-oxadiazol-5-ylcarbonyl)pentyl]-2(RS~-(2'-
chlorobiphen-4-ylcarbonylamino)-3-(2,6-difluorophenyl)propionamide. MS: 656.4
(M-1),
- 658.6 (M+1).
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Compound 13:
N [1(S)-(2-phenyl-[1,3,4]-oxadiazol-5-ylcarbonyl)pentyl]-2(R~-(2'-chlorobiphen-
4-
yl-carbonylamino)-3-(2,6-difluorophenyl)propionamide. MS: 655.4 (M-1), 679.4
(M+Na).
Compound 14:
N [ 1 (S~-benzoxazol-2-ylcarbonylpropyl]-2(~-[2-(2-chlorophenyl)pyridin-5-
ylcarbonylamino]-3-(2,6-difluorophenyl)propionamide. MS: 604.3 (M-H).
Compound 16:
N [1(~-(2-ethyl-[1,3,4]-oxadiazol-5-ylcarbonyl)butyl]-2(RS~-(2'-chlorobiphen-4-
yl-
carbonylamino)-3-(2,6-difluorophenyl)propionamide. 1H-NMR (DMSO-d6): 8.768.54
(m,
2H), 7.906.94 (m, 11H), 5.154.95 (m, 1H), 4.83 (m, 1H), 3.262.92 (m, 2H),
1.901.54
(m, 2H), 1.481.14 (m, SH), 0.940.82 (m, 3H). MS: 581 (M+1).
Compound 18:
N [1(S~-(2-ethyl-[1,3,4]oxadiazol-5-ylcarbonyl)propyl]-2(S~-[2-(2-
chlorophenyl)pyridin-5-ylcarbonylamino]-4(S)phenylpentamide. MS: 575.2 (M+1).
Compound 23:
N [1(~-benzoxazol-2-ylcarbonylpropyl]-2(R~-(4-test-butylphenylcarbonylamino)-
4-ethylhexanoamide. MS: 506.6 (M+1), 504.4 (M-1).
Compound 27:
N [1(S)-benzoxazol-2-ylcarbonylpropyl]-2(~-(2'-chlorobiphen-4-ylcarbonylamino)-
pyrazol-1-ylpropionamide. MS: 5544.5 (M-1), 556.3 (M+1).
Compound 28:
N [1(R~-oxazolo-[4,5-b]-pyridin-2-ylcarbonylpropyl]-2(R)-(2'-chlorobiphen-4-yl-
carbonylamino)-4(S~-phenylpentamide. MS: 593.6 (M-1), 595.2 (M+1).
Compound 29:
- N [1(S')-benzoxazol-2-ylcarbonylpropyl]-2(RS~-(2',3-dichlorobiphen-4-
ylcarbonyl-
amino)-cyclohexylacetamide. MS: 614.3 (M+Na).
Compound 30:
N [1(S')-(2-ethyl-[1,3,4]-oxadiazol-5-ylcarbonylbutyl]-2(S~-(2',3-
dichlorobiphen-4-
yl-carbonylamino)-cyclohexylacetamide. MS: 607.4 (M+Na).
30~ Compound 31:
N [1(S~-benzoxazol-2-ylcarbonylpropyl]-2(S7-(5'-carboxy-2'-chlorobiphen-4-
ylcarbonylamino)-3-(2,6-difluorophenyl)propionamide. 1H-NMR (DMSO-d6): 8 8.81
(m,
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1H), 8.62 (m, 1H), 8.049.98 (m, 14H), 5.27 (m, 1H), 4.87 (m, 1H), 3.403.10 (m,
2H),
2.201.65 (m, 2H), 1.03 (t, 3H), 0.94 (m, 3H). MS: 646 (M+1).
Compound 32:
N [1(~-benzoxazol-2-ylcarbonylpropyl]-2(S~-(4-morpholin-4-
ylphenylcarbonylamino)-4(S)-phenylpentamide. 1H NMR (CDC13): b 8.660 (d, J
8.OHz,
. 1H), 8.526 (s, 1H), 7.960 (d, J 8.OHz, 2H), 7.56-7.59 (m, 1H), 7.521 (d, J
8.2Hz, 2H),
7.434 (m, 2H), 7.24-7.30 (m, 3H), 7.14-7.18 (m, 1H), 4.624 (m, 1H), 2.83-2.92
(m, 1H),
2.660 (m, 2H), 2.316 (q, J--5.8Hz, 2H), 2.217 (m, 4H), 2.00-2.19 (m, 1H), 1.80-
1.95 (m,
3H), 1.231 (d, J 6.4Hz, 3H), 0.971 (t, J 5.8Hz, 3H). MS: 567.4 (M-1), 569.3
(M+1), 591.3
10. (M+Na).
Compound 33:
N [1(~-oxazolo[4,5-b]pyridin-2-ylcarbonylpentyl]-2(RS)-(2'-chlorobiphen-4-
ylcarbonylamino)-3-(2,6-difluorophenyl)propionamide. 1H NMR (DMSO-d6): 8 8.8-
8.55
(m, 3H), 8.45-8.34 (m, 1H), 8.0-7.4 (m, 9H), 7.35-7.2 (m, 1H), 7.1-6.9 (q,
2H), 5.3-5.12 (m,
.. 1H), 4.95-4.78 (m, 1H), 3.3-3.1 (m, 1H), 3.1-2.9 (m, 1H), 2.2-1.8 (m, 1H),
1.8-1.55 (m,
1H), 1.5-1.1 (m, 4H), 0.9-0.8 (m, 3H). MS: 631.2 (M-1), 633.4 (M+1).
Compound 34:
. N [1(S~-benzoxazol-2-ylcarbonylpropyl]-2(,S~-(2'-chlorobiphen-4-
ylcarbonylamino)-
3-(2,4,6-trifluorophenyl)propionamide. 1H NMR (400 MHz, DMSO-d6): 8 7.88-7.09
(m,
12H), 6.55 (m, 2H), 5.62 (m, 1H), 5.10 (m, 1H), 3.28 (dd, J= 14.0, .I--- 5.2
Hz, 1H), 3.47
.. (dd, J= 14.0, J 9.2Hz, 1H), 2.16 (m, 1H), 1.93 (m, 1H), 1.00 (t, J= 7.2Hz,
3H). MS:
620.3 (MH~.
Compound 35:
N [1-(,S')-benzoxazol-2-ylcarbonylpropyl]-2(S~-(1-methyl-3-trifluoro-1H-thieno-
[2,3-
- ~]-pyrazol-5-ylcarbonylamino)-4(~-phenylpentamide. 1H NMR (CDCl3): b 7.79
(d,
. . J 8.4Hz, 1H), 7.60 (d, J 8.4Hz, 1H), 7.35-7.50 (m, 2H), 7.09-7.28 (m, SH),
6.96 (s, 1H),
6.50 (d, J 7.6Hz, 1H), 6.38 (d, J 8.OHz, 1H), 5.49 (m, 1H), 4.38 (m, 1H), 3.95
(s, 3H), 2.86
(m, 1H), 2.10 (m, 3H), 1.82 (m, 1H), 1.21 (d, J 7.2Hz, 3H)), 0.89 (t,.I--
8.OHz, 3H). MS:
6Ø2 (M-1), 612.3 (M+1), 634.6 (M+Na).
30~ 'Compound 36:
N [ 1 (S~-benzoXazol-2-ylcarbonylpropyl]-2(S~-(2'-chlorobiphen-4-
ylcarbonylamino)-
3-thiazol-2-ylpropionamide. 1H NMR (400 MHz, DMSO-d6): ~ 8.42 (d, J= 6.8Hz,
1H),
. 8.30 (d, J=6.8Hz, 1H), 7.96 (d, J= 8.4Hz, 2H), 7.76-7.26 (m, lOH) 5.53 (m,
1H), 5.21 (m,
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1 H), 3 . 83 (dd, J = 15.6, J 4.0 Hz, 1 H), 3 .47 (dd, J = 15.6, 6.8Hz, 1 H),
2.10 (m, 1 H), 1.91
(m, 1H), 0.92 (t, J= 7.2Hz, 3H). MS: 573.2(MH+ ).
Compound 37:
N [ 1 (R,S')-benzoxazol-2-ylcarbonylpropyl]-2(,S')-[2-(2-chlorophenyl)pyridin-
5-
ylcarbonylamino)-3-thiazol-2-ylpropionamide. 1H NMR (DMSO-d6): b 9.08 (d, 1H),
9.02
(~, 1H), 8.88 (d,d, 1H), 8.21 (m, 1H), 7.98-7.93 (m, 1H), 7.89-7.83 (m, 1H),
7.76-7.72 (m,
1 H), 7.68 (d, 1 H), 7.64-7.43 (m, 7H), 5.25-5.17 (m, 1 H), 5.08-4.96 (m, 1
H), 3.7-3.5 (m,
1H), 3.5-3.3 (m, 1H), 2.1-1.95 (m, 1H), 1.85-1.65 (m, 1H), 0.99 (t, 3H). MS:
572.1 (M-1),
574.2 (M+1).
Compound 38:
N [1-(S~-benzoxazol-2-ylcarbonylpropyl]-(2~-[2-(2-chlorophenyl)pyridin-5-yl-
. carbonylamino)-3-thiazol-2-ylpropionamide. 1H NMR (400 MHz, DMSO-d6): 8 9.24
(dd, J
= 2.8, 0.8Hz, 1H), 8.65 (d, J=6.8Hz, 1H), 8.28-7.25 (m, 11H), 5.54 (m, 1H),
5.21 (m, 1H),
3 . 84 (dd, J = 15 . 6, 4. 0 Hz, 1 H), 3 .46 (dd, J = 15 . 6, 6. 8 Hz, 1 H),
2.14 (m, 1 H), 1.91 (m, 1 H),
~ 0.92 (t, J= 8.OHz, 3H). MS: 574.1 (MH~.
Compound 39:
N [ 1 (,S')-benzoxazol-2-ylcarbonylpropyl]-2(S~-(3-vinylphenylcarbonylamino)-
4S-
phenylpentamide. 1H NMR (CDCl3): 8 7.40-7.53 (m, 3H), 6.90-7.40 (m, 9H), 6.55-
6.80 (m,
3H), 5.55-5.95 (m, 2H), 5.30 (m, 1H), 4.10-4.55 (m, 1H), 2.98 (m, 1H), 2.75-
2.95 (m, 1H),
2.15 (m, 2H), 1.70-1.95 (m, 2H), 1.25 (m, 3H), 1.00 (m, 3H). MS: 508.1 (M-1),
532.2
(M+Na).
Compound 41:
N [1(,S~-benzoxazol-2-ylcarbonylpropyl]-2(,S~-(4-acetylamino-3-
methylphenylcarbonyl-amino)-4S-phenylpentamide. 1H NMR (CDC13): S 7.99 (d, J
7.6Hz,
~ 1H), 7.87 (d, J 6.OHz, 1H), 7.67 (d, J 7.6Hz, 2H), 7.56 (m, 2H), 7.39-7.50
(m, 3H), 7.24-
7.33 (m, 2H), 7.19 (m, 1H), 7.09 (m, 1H), 6.70 (d, J 6.4Hz, 1H), 6.54 (d, J
7.6Hz, 1H),
5.57 (m, 1H), 4.51 (m, 1H), 2.92 (m, 1H), 2.27 (s, 3H), 2.23 (m, 3H), 2.08-
2.14 (m, 1H),
2.05 (m, 2H), 1.87 (m, 1H), 1.27 (m, 3H), 0.95 (m, 3H). MS: 553.4 (M-1), 555.5
(M+1),
577.4 (M+Na).
- Compound 42:
N [1(S')-2-phenyl[1,3,4]oxadiazol-5-ylcarbonylpropyl]-2(S')-(2'-chlorobiphen-4-
ylcarbonylamino)-2-cyclohexylacetamide. Hl NMR (DMSO-d6): 8 8.75 (d, 1H), 8.39
(d,
1H), 8.1 (d, 2H), 7.9 (d, 2H), 27.7-7.5 (m, 4H), 7.5-7.3 (m, SH), 5.1-4.9 (m,
1H), 4.5-4.3 (t,
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l,H), 2.1-1.95 (m, 1H); 1.9-1.5 (m, 8H), 1.1-1 (m, 4H), 0.99 (t, 3H). MS:
585.3 (M+1),
607.4 (M+Na).
Compound 43:
N [ 1 (~-benzoxazol-2-ylcarbonylpropyl]-2(~-(2'-chlorobiphen-4-
ylcarbonylamino)-
3rindol-3-ylpropionamide. 1H-NMR (DMSO-d6): 8 8.80 (m, 1H), 8.60 (m, 1H),
8.067.0
(m, 17H), 5.28 (m, 1H), 4.86 (m, 1H), 3.403.05 (rn, 2H), 2.081.68 (m, 2H),
1.060.86
(m, 3H). MS: 605 (M+1).
Compound 44:
N [1(S')-benzoxazol-2-ylcarbonylpropyl]-2(,S~-(2'-chlorobiphen-4-
ylcarbonylamino)-
3-(N phenyl-N methylamino)propionamide. 1H NMR (DMSO-d6): 8 7.8-7.7 (m, 3H),
7.6
. (d, 1H), 7.55-7.45 (m, 1H), 7.45-7.35 (m, 5H), 7.32 (d, 1H), 7.28-7.2 (m,
3H), 7.15-7.05 (m,
. 3H), 6.85 (d, 1H), 6.57 (t, 1H), 5.5-5.4 (m, 1H), 4.92-4.8 (m, 1H), 3.83
(d,d, 1H), 3.39 (d,d,
lH), 2.96 (s, 3H), 2.1-2 (m, 1H), 1.9-1.79 (m, 1H), 0.88 (t, 3H). MS: 593.3(M-
1), 595.5
(M+1).
_ Compound 45:
N [1-(~-2-phenyl[1,3,4]oxadiazol-5-ylcarbonylpropyl]-2(S~-(2',3-dichlorobiphen-
4-
ylcarbonylamino)-2-cyclohexylacetamide. 1H NMR (DMSO-d6): 8 8.8 (d, 1H), 8.45
(d,
1 H), 8.05-7.9 (m, 3 H), 7.8 (d, 1 H), 7.7-7.2 (m, 8H), 5.1-4.9 (m, 1 H), 4.4
(t, 1 H), 2.1-1.9 (m,
1H), 1.8-1.4 (m, 7H), 1.3-0.8 (m, 8H). MS: 641.3 (M+Na).
~ Compound 46:
N [1(S~-2-test-butyl[1,3,4]oxadiazol-5-ylcarbonylbutyl]-2(R~-(2'-chlorobiphen-
4-
ylcarbonylarnino)-3-(2,6-difluorophenyl)propionamide. 1H-NMR (DMSO-d6): 8
8.768.54
(m, 2H), 7.926.94 (m, 11 H), 5.04 (m, 1 H), 4.82 (m, 1 H), 3.282.98 (m, 2H),
1.901.54
(m, 2H), 1.481.14 (m, 9H), 0.940.82 (m, 3H). MS: 609 (M+1).
Compound 47:
N [1(~-benzoxazol-2-ylcarbonylpropyl]-2(,S~-[3,5-di(2-
methoxyphenyl)phenylcarbonyl-amino]propionamide. 1H NMR (DMSO-d6): 8 8.58 (s,
2H), 8.007.04 (m, 15H), 5.21 (m, 1H), 4.60 (m, 1H), 3.76 (s, 6H), 2.02 (m,
1H), 1.76 (m,
1H), 0.89 (d, J 20Hz, 6H). MS: 592 (M+1).
w ~ Compound 48:
N [1(~-benzoxazol-2-ylcarbonylpropyl]-2(R~-(2'-chlorobiphen-4-
ylcarbonylamino)-3-(4-methylindol-3-yl)propionamide. 1H-NMR (DMSO-d6): b
8.648.72
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(m, 2H), 8.106.68 (m, 14H), 5.24 (m, 1H), 4.82 (m, 1H), 2.62 (m, 2H), 2.181.70
(m, 3H),
1.300.76 (rn, SH). MS: 619 (M+1).
Compound 49:
N [1(S)-benzoxazol-2-ylcarbonylpropyl]-2(~-(5'-carboxy-2'-chlorobiphen-4-
5. ylcarbonylamino)propionarnide. IH-NMR (DMSO-d6): b 8.648.52 (m, 2H),
8.007.8 (m,
6H), 7.747.50 (m, SH), 5.23 (m, 1H), 4.60 (m, 1H), 2.01 (m, 1H), 1.76 (m, 1H),
1.35 (t,
3H), 0.99 (m, 3H). MS: 534 (M+1).
Compound 50:
N [1(RS7-2-phenyl[1,3,4]oxadiazol-5-ylcarbonylpropyl]-2(R)-(2'-chlorobiphen-4-
ylcarbonylamino)-4S-phenylpentamide. 1H NMR (DMSO-d6): ~ 8.65-8.5 (m, 2H),
8.15-
8.02 (m, 2H), 7.95-7.83 (m, 2H), 7.72-7.52 (m, 4H), 7.52-7.35 (m, SH), 7.3-
7.16 (m, 3H),
7.16-7.08 (m, 2H), 5.07-4.949 (m, 1H), 4.17 (m, 1H), 2.85-2.79 (m, 1H), 2.0-
1.8 (m, 3H),
1.8-1.65 (m, 1H), 1.25-1.1 (d, 3H), 0.92 (t, 3H). MS: 519.6(M-1), 621.3 (M+1),
643.5
(M+Na).
~ Compound 51:
N [1(,S~-benzoxazol-2-ylcarbonylpropyl]-2(,S~-(2',3-dichlorobiphen-4-
ylcarbonylamino)-propionamide. 1H NMR (DMSO-d6): 8 8.70 (m, 1H), 8.61 (m, 1H),
8.107.30 (m, lOH), 5.20 (m, 1H), 4.59 (m, 1H), 2.01 (m, 1H), 1.76 (m, 1H),
1.35 (t, 3H),
1.01 (m, 3H). MS: 524 (M+1).
Compound 54:
2'-Chlorobiphen-4-ylcarboxylic acid {1-[1(S')-oxazolo[4,5-b]pyridin-2-
ylcarbonyl)-
propylaminocarbonyl]cycloheptyl}amide; NMR: S 9.2 (s, 1H), 8.78 (s, 1H), 8.45
(d, J-
6.8Hz, 1H), 8.20 (s, 1H), 7.9 (d, J 8.0 Hz, 2H), 7.40-7.70 (m, 8H), 5.38 (s,
1H), 1.05-2.2
(m, 17H). MS: M-1 (558.6).
~ Compound 55:
2',3-Dichlorobiphen-4-ylcarboxylic acid {1-[1(~-oxazolo[4,5-b]pyridin-2-
ylcarbonyl)-propylaminocarbonyl]cycloheptyl}amide MS: M-1 (592.1).
. Compound 56:
2',3-Dichlorobiphen-4-ylcarboxylic acid {1-[1-benzoxazol-2-ylcarbonyl)propyl-
... aminocarbonyl]cycloheptyl}amide MS: M-2 (590.1).
Biological Exa ales
Example 1
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Cathepsin B Assay
Solutions of test compounds in varying concentrations were prepared in 10 pL
of
dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 ~L,
comprising: N,N
bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 50 mM (pH 6);
5- polyoxyethylenesorbitan monolaurate, 0.05%; and dithiothreitol (DTT), 2.5
mM). Human
cathepsin B (0.025 pMoles in 25 ~,I, of assay buffer) was added to the
dilutions. The assay
solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated
for 30
minutes at room temperature. Z-FR-AMC (20 nMoles in 25 p,L, of assay buffer)
was added
to the assay solutions and hydrolysis was followed spectrophotometrically at
(~, 460 nm) for
5'minutes. Apparent inhibition constants (K;) were calculated from the enzyme
progress
curves using standard mathematical models.
Compounds of the invention were tested by the above-described assay and
observed
to exhibit cathepsin B inhibitory activity.
- Example 2
Cathepsin K Assay
Solutions of test compounds in varying concentrations were prepared in 10 ~L
of
dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 ~L,
comprising: MES,
50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM). Human cathepsin K (0.0906
pMoles
20. ~ in 25 ~I, of assay buffer) was added to the dilutions. The assay
solutions were mixed for 5-
10 seconds on a shaker plate, covered and incubated for 30 minutes at room
temperature.
Z-Phe-Arg-AMC (4 nMoles in 25 ~L of assay buffer) was added to the assay
solutions and
hydrolysis was followed spectrophotometrically at (~, 460 nm) for 5 minutes.
Apparent
inhibition constants (K;) were calculated from the enzyme progress curves
using standard
25- mathematical models.
Compounds of the invention were tested by the above-described assay and
observed
tb exhibit cathepsin K inhibitory activity.
Example 3
30. Cathepsin L Assay
Solutions of test compounds in varying concentrations were prepared in 10 ~,L
of
dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 ~,L,
comprising: MES,
50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM). Human cathepsin L (0.05 pMoles
in
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25 ~L of assay buffer) was added to the dilutions. The assay solutions were
mixed for 5-10
seconds on a shaker plate, covered and incubated for 30 minutes at room
temperature. Z-
Phe-Arg-AMC (1 nMoles in 25 ~,L of assay buffer) was added to the assay
solutions and
hydrolysis was followed spectrophotometrically at (~, 460 nm) for 5 minutes.
Apparent
5~ inhibition constants (K;) were calculated from the enzyme progress curves
using standard
riiathematical models.
Compounds of the invention were tested by the above-described assay and
observed
to exhibit cathepsin L inhibitory activity.
~ Example 4
Cathepsin S Assay
a . Solutions of test compounds in varying concentrations were prepared in 10
~,L of
dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 ~,L,
comprising: MES,
50 mM (pH 6.5); EDTA, 2.5 mM; and NaCI, 100 mM); (3-mercaptoethanol, 2.5 mM;
and
B,SA, 0.00%. Human cathepsin S (0.05 pMoles in 25 ~I. of assay buffer) was
added to the
dilutions. The assay solutions were mixed for 5-10 seconds on a shaker plate,
covered and
incubated for 30 minutes at room temperature. Z-Val-Val-Arg-AMC (4 nMoles in
25 wL of
~, , assay buffer containing 10% DMSO) was added to the assay solutions and
hydrolysis was
followed spectrophotometrically (at 7~ 460 nm) for 5 minutes. Apparent
inhibition constants
29 ~ (K;) were calculated from the enzyme progress curves using standard
mathematical models.
Compounds of the invention were tested by the above-described assay and
observed
to exhibit cathepsin S inhibitory activity.
Example 5
. Cathepsin F Assay
' , Solutions of test compounds in varying concentrations were prepared in 10
~L of
dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 ~,L,
comprising: MES,
50 mM (pH 6.5); EDTA, 2.5 mM; and NaCI, 100 mM); DTT, 2.5 mM; and BSA, 0.01%.
. , Human cathepsin F (0.1 pMoles in 25 pL of assay buffer) was added to the
dilutions. The
~ assay solutions were mixed for 5-10 seconds on a shaker plate, covered and
incubated for
30 minutes at room temperature. Z-Phe-Arg-AMC (2 nMoles in 25 E.iL of assay
buffer
v containing 10% DMSO) was added to the assay solutions and hydrolysis was
followed
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spectrophotometrically (at ~, 460 nm) for 5 minutes. Apparent inhibition
constants (K;)
were calculated from the enzyme progress curves using standard mathematical
models.
Compounds of the invention were tested by the above-described assay and
observed
to exhibit cathepsin F inhibitory activity.
Pharmaceutical Composition Examples
The following are representative pharmaceutical formulations containing a
compound of Formula I.
' . Tablet Formulation
The following ingredients are mixed intimately and pressed into single scored
tablets.
' Quantity per
~ Ingredient tablet, mg
compound of this invention 400
cornstarch 50
croscarmellose sodium 25
. lactose 120
. ' magnesium stearate 5
Capsule Formulation
The following ingredients are mixed intimately and loaded into a hard-shell
gelatin
25. capsule.
Quantity per
Ingredient capsule, mg
compound of this invention 200
lactose, spray-dried 148
. magnesium stearate 2
Suspension Formulation
The following ingredients are mixed to form a suspension for oral
administration.
3 5. ~ Ingredient Amount
. compound of this invention 1.0 g
. ' fumaric acid 0.5 g
sodium chloride 2.0 g
methyl paraben 0.15 g
. propyl paraben 0.05 g
granulated sugar 25.5 g
sorbitol (70% solution) 12.85 g
Veegum K (Vanderbilt Co.) 1.0 g
flavoring 0.035 mL
. colorings 0.5 mg
distilled water q.s. to 100 mL
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Injectable Formulation
The following ingredients are mixed to form an injectable formulation.
- Ingredient Amount
~ compound of this invention 1.2 g
sodium acetate buffer solution, 0.4 M 2.0 mL
HCl (1 N) or NaOH (1 N) q.s. to suitable
pH
water (distilled, sterile) q.s.to 20 mL
All of the above ingredients, except water, are combined and heated to 60-70
°C
with stirnng. A sufficient quantity of water at 60 °C is then added
with vigorous stirring
to emulsify the ingredients, and water then added q.s. to 100 g.
Suppository Formulation
. A suppository of total weight 2.5 g is prepared by mixing the compound of
the
invention with Witepsol® H-15 (triglycerides of saturated vegetable fatty
acid;
Riches-Nelson, Inc., New York), and has the following composition:
compound of the invention 500 mg
Witepsol~ H-15 balance
The foregoing invention has been described in some detail by way of
illustration
and example, for purposes of clarity and understanding. It will be obvious to
one of skill
in the art that changes and modifications may be practiced within the scope of
the
appended claims. Therefore, it is to be understood that the above description
is intended
- to be illustrative and not restrictive. The scope of the invention should,
therefore, be
determined not with reference to the above description, but should instead be
determined with reference to the following appended claims, along with the
full scope of
equivalents to which such claims are entitled.
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